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Immunity. Author manuscript; available in PMC 2017 May 17. Published in final edited form as: Immunity. 2016 May 17; 44(5): 1034–1051. doi:10.1016/j.immuni.2016.04.017.
Co-stimulatory and co-inhibitory pathways in autoimmunity Qianxia Zhang1 and Dario A.A. Vignali1,2,* 1Department 2Tumor
of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232,
USA
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Abstract
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The immune system is guided by a series of checks and balances, a major component of which is a large array of co-stimulatory and co-inhibitory pathways that modulate the host response. While co-stimulation is essential to boost and shape the initial response following signaling through the antigen receptor, inhibitory pathways are also critical to modulate the immune response. Excessive co-stimulation and/or insufficient co-inhibition can lead to a breakdown of self-tolerance, leading to autoimmunity. In this review, we will focus on the role of co-stimulatory and co-inhibitory pathways in two systemic (Systemic Lupus Erythematosus and Rheumatoid Arthritis) and two organ-specific (Multiple Sclerosis and Type 1 Diabetes) autoimmune diseases that are emblematic. We will also discuss how mechanistic analysis of these pathways has led to the identification of potential therapeutic targets and initiation of clinical trials for autoimmune diseases, as well as outline some of the challenges that lie ahead.
Introduction
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Immunological self-tolerance is the unresponsiveness of the immune system to self-antigens (self-Ags). A breakdown in immune homeostasis and self-tolerance leads to autoimmunity, resulting in deleterious inflammation in, and destruction of, self-tissues mediated by autoreactive T cells and autoantibodies (auto-Abs) (Goodnow et al., 2005; Schwartz, 1989). In order to prevent autoimmunity, an intricate series of molecular checks and balances helps to ensure that the immune system produces a measured and appropriate response to foreign threats while avoiding host tissue pathology and destruction. However, emerging observations suggest that these control mechanisms are subverted in autoimmunity, providing underlying mechanistic insight while also pointing to potential avenues for therapeutic intervention. The Two-Signal model proposes that activation of naïve T cells requires both T cell receptor (TCR) stimulation by MHC:peptide complexes [Signal 1] and co-stimulation via costimulatory receptors and their corresponding ligands on antigen presenting cells (APCs)
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[Signal 2] (Lafferty and Cunningham, 1975; Mueller et al., 1989). For instance, one of the most prominent co-stimulatory pathways is the CD28:B7 axis that amplifies TCR signaling and interleukin-2 (IL2) production to promote T cell proliferation and survival. In order to provide a mechanism to turn off T cell activation, co-inhibitory receptors are induced by TCR stimulation and co-stimulation and subsequently transduce feedback signals that dampen the ascending co-stimulatory signals. Therefore, the net outcome of TCR stimulation is modified by both co-stimulatory and co-inhibitory receptors. Both sets of receptors are expressed by all T cell subsets thereby helping to shape the overall immune response. For instance, they are also expressed by, and have critical impact on, regulatory T (Treg) cells, an immunosuppressive population that plays a pivotal role in self-tolerance (Sakaguchi et al., 2008; Vignali et al., 2008). Excessive co-stimulation and/or inadequate coinhibition results in aberrant T cell activation, which can result in a breakdown of selftolerance by activating and expanding autoreactive T cells. Similarly, B cells and other immune cells also require two signals for their activation, maturation and function (Bretscher and Cohn, 1970). Therefore, the immune response is fundamentally shaped and modulated by co-stimulatory and co-inhibitory receptors and their corresponding ligands. Disruption of the balance between co-stimulation and co-inhibition unleashes self-reactivity leading to autoimmune disease.
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While co-stimulatory and co-inhibitory pathways have a significant impact on all autoimmune diseases, in the interest of brevity, in this review we will focus on their role in two systemic (Systemic Lupus Erythematosus and Rheumatoid Arthritis) and two organspecific (Multiple Sclerosis and Type 1 Diabetes) autoimmune diseases of major importance and interest that are emblematic of other autoimmune diseases. More general aspects of the role of these pathways in T cell development and function, and in other diseases have been discussed in other reviews ([Au: with this statement, do you want to call out all the other pieces? Sharpe, Kuchroo, Bluestone, Ware, Wherry, Ford, Wolchok) We will also discuss how mechanistic analysis of co-stimulatory and co-inhibitory pathways using a wide variety of animal models and human studies has led to the identification of potential therapeutic targets and initiation of clinical trials for autoimmune diseases, as well as outline some of the challenges that lie ahead.
Systemic Lupus Erythematosus
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Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disorder associated with the presence of anti-nuclear antibodies (Abs) and the combinatorial clinical manifestations of rash, thrombocytopenia, serositis, and nephritis (Lisnevskaia et al., 2014). Lupus nephritis (LN, glomerulonephritis) is a key feature of SLE, marked by inflammation of, and auto-Ab accumulation in, the kidney. The dysregulation of B and T cell activation leads to auto-Ab production, immune complex (IC) formation, and multi-organ damage in SLE (Lisnevskaia et al., 2014). ICs are central players in tissue damage in SLE, and T cells are critical participants in the breakdown of B cell tolerance. Follicular helper T (Tfh) cells are professional helper cells that facilitate germinal center (GC) formation, B cell development, and B cell receptor (BCR) affinity maturation (Crotty, 2014). Aberrant Tfh cell differentiation and activation drives the pathogenesis of many systemic autoimmune diseases including SLE. Immunity. Author manuscript; available in PMC 2017 May 17.
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The spontaneous murine lupus models, F1 hybrid of New Zealand Black and New Zealand White (NZB/NZW.F1) and MRL mice hom*ozygous for the lymphoproliferation gene (MRL-lpr), are commonly used to study the role of co-stimulatory and co-inhibitory pathways in SLE. NZB/NZW.F1 mice develop IC-mediated glomerulonephritis with elevated anti-nuclear Ab titers, representing a model of the chronic lupus disorder (Crampton et al., 2014). MRL-lpr mice exhibit a more severe lupus-like syndrome with B cell hyperactivity, circulating ICs, and a wide range of auto-Abs (Crampton et al., 2014). Other mouse models of SLE have been developed but will not be discussed here.
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Several co-stimulatory pathways have been shown to impact the development of lupus. The co-stimulatory receptor CD28 is activated by its ligands B7.1 (CD80) and B7.2 (CD86), and couples with TCR signaling to promote T cell proliferation and survival during T cell priming. Cd28−/− MRL-lpr mice exhibit delayed and diminished glomerulonephritis and an absence of renal vasculitis and arthritis (Tada et al., 1999a), implying that blocking CD28:B7 interactions may be a potential treatment for autoimmune lupus. However, B7.1 and B7.2 appear to function in a redundant manner, as treatment with both anti-B7.1 and anti-B7.2 significantly reduced auto-Ab production whereas blocking either B7.1 or B7.2 alone had a minimal effect on auto-Ab levels in MRL-lpr mice (Liang et al., 1999). Interestingly, Cd80−/− but not Cd86−/− MRL-lpr mice exhibited more severe glomerulonephritis than wild-type controls (Liang et al., 1999), raising the possibility that B7.1 also has inhibitory activity in this setting which could either be due to preferential interactions with the co-inhibitory receptor CTLA4 (CD152) over B7.2, or due to interactions with another co-inhibitory receptor PD-L1 (B7-H1, CD274) (Butte et al., 2007). CTLA4Ig, a fusion protein composed of the murine CTLA4 extracellular domain and IgG2a Fc, inhibits CD28:B7 interactions by binding to B7 molecules with a higher affinity. CTLA4Ig administration prolonged the survival of NZB/NZW.F1 mice by preventing autoAb production, limiting immunoglobulin class switching and somatic mutation, and reducing CD4+ T cell activation (Finck et al., 1994; Mihara et al., 2000). However, clinical trials of Abatacept [a fusion protein of the human CTLA4 extracellular domain and IgG1 Fc] in SLE patients have yet to exhibit any clear efficacy, although it was well tolerated (Furie et al., 2014; Group, 2014; Merrill et al., 2010).
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Even though a protective effect was seen in Cd28−/− MRL-lpr mice, the accumulation of autoreactive T cells was unaffected (Tada et al., 1999a), implying that additional T cell costimulatory pathways are exploited in SLE. The co-stimulatory receptor ICOS (CD278) is essential for T cell activation and promotes humoral immunity (Dong et al., 2001). The generation, function and maintenance of Tfh and extrafollicular helper T cells that help GC formation, B cell maturation and IgG production are ICOS-dependent in both NZB/NZW.F1 and MRL-lpr mice (Hu et al., 2009; Odegard et al., 2008; Teichmann et al., 2015). Given the importance of ICOS in promoting SLE pathogenesis, the safety and efficacy of AMG 557, a human Ab that targets the ICOS ligand (ICOSL, B7-H2, CD275), is currently being evaluated in clinical trials with SLE patients. Members of the tumor necrosis factor superfamily (TNFSF) and tumor necrosis factor receptor superfamily (TNFRSF) play a dominant role in the pathogenesis of many autoimmune diseases. The interaction between B and T cells via the CD40
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(TNFRSF5):CD40L (TNFSF5, CD154) axis provides critical activation signals for thymusdependent humoral immunity in SLE. Loss of CD40:CD40L signaling ameliorated disease severity and prolonged survival of both NZB/NZW.F1 and MRL-lpr mice (Early et al., 1996; Ma et al., 1996). Signals transduced by co-stimulatory receptors and their corresponding ligands-receptors are often reciprocal. Indeed, ligation of CD40L with CD40 not only activates T cells but also promotes B cell class switching and somatic mutation in NZB/ NZW.F1 mice (Wang et al., 2003). However, anti-CD40L in SLE clinical trials has exhibited mixed results thus far (Boumpas et al., 2003; Kalunian et al., 2002). It is possible that redundant pathways are involved in promoting auto-Ab production in SLE, as indicated by the existence of isotype switching in Cd154−/− MRL-lpr mice (Ma et al., 1996). AntiCD40L blockade in combination with CTLA4Ig in NZB/NZW.F1 mice showed synergistic effects in the delay of lupus onset by suppressing both autoreactive B and T cells (Daikh et al., 1997; Wang et al., 2002), suggesting that combinatorial approaches might enhance efficacy.
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Other co-stimulatory pathways are also involved in the pathogenesis of SLE. Polymorphism at TNFSF4 (OX40L, CD252) is associated with abnormal expression in SLE patients, and has been fine mapped to one of the SLE-susceptibility loci (Cunninghame Graham et al., 2008; Manku et al., 2013). It was suggested that the OX40 (TNFRSF4, CD134):OX40L costimulation axis contributes to SLE pathogenesis by promoting Tfh responses (Jacquemin et al., 2015). Interestingly, another TNFRSF member, 4-1BB (TNFRSF9, CD137), delivers costimulatory signals to T cells, but paradoxically a protective role for 4-1BB has been suggested in murine lupus models. Cd137−/− MRL-lpr mice exhibited pronounced lymphadenopathy and early mortality with increased CD4+ T cell number and B cell function (Vinay et al., 2007). Treatment with 4-1BB agonist Ab resulted in IFNγ-dependent depletion of autoreactive B cells, reduced auto-Ab production and prolonged survival of MRL-lpr mice (Sun et al., 2002a). In contrast, agonistic anti-4-1BB treatment of NZB/ NZW.F1 mice did not alter the frequency of T or B cells, but suppressed GC formation and anti-dsDNA IgG production (Foell et al., 2003). These studies suggest that 4-1BB agonist could be a potential therapeutic agent for SLE, although additional studies will be required to fully understand its impact in different models of SLE.
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While aberrant co-stimulation promotes the development of SLE, co-inhibitory pathways are required to limit SLE pathogenesis. PD1 (CD279) is the most studied co-inhibitory receptor in SLE and has two ligands, PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273). Polymorphisms at PDCD1 have been reported to be associated with susceptibility to SLE (Okazaki and Honjo, 2007). It has been suggested that Pdcd1−/− C57BL/6J mice have elevated levels of IgG2b, IgA, and IgG3 in their sera and reduced expression of CD5, a negative regulator of B1 cell activation (Nishimura et al., 1998). Aged Pdcd1−/− C57BL/6J mice spontaneously developed lupus-like autoimmune symptoms and introduction of the lpr mutation facilitated lupus onset (Nishimura et al., 1999). Controversially, while blockade with anti-PD-L1 accelerated LN onset, PD1 blockade limited LN in NZB/NZW.F1 mice and promoted the suppressive capacity of both CD4+ and CD8+ Treg cells (Kasagi et al., 2010; Wong et al., 2013; Wong et al., 2010). Interestingly, it has been suggested that the PD1 pathway regulates Tfh-mediated humoral immunity by suppressing follicular regulatory T
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(Tfr) cells (Sage et al., 2013), raising the possibility that PD1 blockade is mitigating lupus manifestations by preferentially impacting PD1 function on Tfr cells.
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A protective role for other co-inhibitory receptors of the immunoglobulin superfamily (IgSF) has also been suggested in SLE. For instance, increased serum concentrations of soluble CTLA4 were found in SLE patients (Saverino et al., 2010). A polymorphism at the CTLA4 promoter was also reported to be associated with SLE susceptibility in an Asian population (Taha Khalaf et al., 2011). Overexpression of an alternatively spliced CTLA4 isoform lacking both the ligand binding domain and the transmembrane domain (1/4CTLA4), encoded by exons 2 and 3, precipitated lupus onset in MRL-lpr mice (Ichinose et al., 2013). A recent study has shown that CTLA4 controls humoral responses by modulating Tfh, Tfr and Treg cells (Sage et al., 2014), raising the possibility that expression of CTLA4 on these T cell subsets is essential to prevent SLE. BTLA (CD272) is another IgSF co-inhibitory receptor. Btla−/− MRL-lpr mice exhibited exacerbated lupus-associated disorders with elevated auto-Ab production and massive organ infiltration of inflammatory cells (Oya et al., 2011). These studies suggest that co-inhibitory pathways are utilized to protect against autoimmunity in SLE despite the malfunctioned co-stimulatory pathways.
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It is noteworthy that co-stimulatory receptors of the signaling lymphocyte activation molecule family (SLAMF) have been of considerable interest recently in SLE due to their critical role in Tfh cell function (Crotty, 2014). Slamf6 (Ly108, CD352) is encoded within the NZW-derived sle1 lupus-susceptibility locus (Crampton et al., 2014). Signaling via SLAMF6 promoted Th1 cytokine production by T cells from SLE patients (Chatterjee et al., 2011). It has been suggested that SLAMF6 transduces co-inhibitory signals by binding with SHP-1, while the Tfh cell help to B cells is dependent on SLAMF6 binding with SLAMassociated protein (SAP) (Kageyama et al., 2012). Interestingly, the protective SLAMF6 isoform was not present in the lupus-prone congenic mice (Keszei et al., 2011), raising the possibility that SLE patients are more likely to express the isoform that preferentially binds SAP. The role of other SLAMF receptors has also been suggested in both murine models and SLE patients (Brown et al., 2011; Koh et al., 2011). However, further studies need to be performed to fully understand the impact of SLAM family receptors in SLE. While the full impact of co-inhibitory pathways in SLE is less well understood, costimulatory signals do appear to be exacerbated in this disease (Figure 1). Given the major contribution of autoreactive B and Tfh cells in SLE pathogenesis, co-stimulatory and coinhibitory pathways that affect B and Tfh cell differentiation and functions (such as the ICOS, CD40 and SLAM pathways) are likely to have a major impact on SLE development, and thus may be potential therapeutic targets in the treatment of SLE.
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Rheumatoid Arthritis Rheumatoid Arthritis (RA) is a systemic autoimmune disease characterized by auto-Ab production, synovial inflammation and hyperplasia, cartilage and bone destruction in multiple joints, and cardiovascular and pulmonary disorders (Burmester et al., 2014). The early stages of RA present with local inflammation in the joints, which subsequently develops into a systemic disorder due to the loss of immune tolerance. Pathogenic T cells
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not only help B cells produce auto-Abs [rheumatoid factor and anti-citrullinated protein], but also actively mediate tissue destruction by secreting proinflammatory cytokines [IL17, IL6 and TNFα] and creating an inflammatory microenvironment that favors macrophage and neutrophil recruitment, and osteoclast activation (Burmester et al., 2014).
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Numerous murine models of RA have been used to understand the etiology and pathogenesis of this disease (Bevaart et al., 2010; van den Berg, 2009). One of the most commonly used models is collagen-induced arthritis (CIA). Collagen type II-immunized DBA/1 mice develop polyarthritis characterized by synovial inflammation and hyperplasia, and cartilage and bone erosion, similar to the manifestations seen in RA patients. Less frequently utilized models discussed here include the proteoglycan-induced arthritis (PGIA) and Il1ra−/− BALB/c mouse models. The latter exhibit synovial inflammation and articular erosion. IC formation and autoreactive T cells are present in all three models. Other mouse models of RA have been developed but will not be discussed here.
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Multiple co-stimulatory pathways have been studied in RA, with the CD28:B7 costimulatory pathway playing an indispensible role. Cd28−/− DBA/1 mice were resistant to arthritis after standard collagen II immunization and only a very small percentage of Cd28−/− mice developed CIA after augmented Ag loading (Tada et al., 1999b), suggesting a prerequisite role of CD28 co-stimulation in autoreactive T cell priming in CIA. It was also suggested that the expression of B7 molecules on B cells was essential for autoreactive T cell priming in PGIA (O’Neill et al., 2007). Similar to observations in models of SLE, B7.1 and B7.2 seem to activate CD28 co-stimulation in a redundant manner in CIA (Webb et al., 1996). Blocking CD28:B7 interactions with CTLA4Ig before or at the time of immunization prevented the development of CIA, while administration of CTLA4Ig after arthritis onset was able to ameliorate CIA (Knoerzer et al., 1995; Quattrocchi et al., 2000; Webb et al., 1996). In addition to reduced lymphocyte expansion and pro-inflammatory cytokine production, CTLA4Ig treatment also induced Treg cells by generating tolerogenic dendritic cells (DCs) in the CIA model (Ko et al., 2010). In contrast to SLE, clinical trials with Abatacept (human CTLA4Ig) were more successful in RA patients, and Abatacept was approved by the US FDA (Food and Drug Administration) to treat RA based on long-term safety and efficacy results (Ford et al., 2014). Importantly, Abatacept treatment resulted in clinical benefits in RA patients refractory to other RA treatments (Genovese et al., 2005; Westhovens et al., 2014), and was able to sustain disease remission after withdrawal of therapy in recent-onset RA patients (Emery et al., 2015).
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Although CD28:B7 co-stimulation plays an essential role in the pathogenesis of RA, autoAb production by B cells remains intact in the absence of CD28:B7 signaling, suggesting that other co-stimulatory receptors contribute to the disease (O’Neill et al., 2007; Tada et al., 1999b). Indeed, the protective effect of CD28:B7 perturbation was diminished by the presence of proinflammatory cytokines, such as IL12 in the CIA model and IL1 in the spontaneous Il1ra−/− RA model (Kotani et al., 2006; Tada et al., 1999b), suggesting that CD28-independent co-stimulatory pathways are provoked by proinflammatory cytokines during RA pathogenesis. Interestingly, ICOSL is induced by TNFα (Swallow et al., 1999), a dominant cytokine in RA, raising the possibility that the ICOS:ICOSL pathway is activated during RA pathogenesis. Blockade with anti-ICOSL resulted in mitigated CIA and reduced
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auto-Ab titers (Iwai et al., 2002). ICOS:ICOSL co-stimulation contributes to CIA induction by promoting Tfh cell generation, GC formation and auto-Ab production (Hu et al., 2009), suggesting that this pathway may be responsible for the maintenance of an auto-Ab response in CIA induced in Cd28−/− mice (O’Neill et al., 2007; Tada et al., 1999b). The CD40:CD40L axis also contributes to auto-Ab production in RA. CD40L was expressed on CD4+ T cells from synovial fluid of RA patients following in vitro activation and promoted auto-Ab production (MacDonald et al., 1997). CD40:CD40L blockade abrogated rheumatoid factor production in transgenic mice overexpressing human rheumatoid factor, whereas a CD40 agonist Ab prevented apoptosis of rheumatoid factor precursor B cells in CIA (Kyburz et al., 1999; Tellander et al., 2000). Thus it is likely that the ICOS:ICOSL and CD40:CD40L pathways contribute to RA pathogenesis by promoting humoral immunity.
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Other TNFRSF co-stimulatory pathways have also been studied in RA using the CIA model. The expression of OX40 on activated T cells and OX40L predominantly on APCs is restricted to inflamed joints (Gwyer Findlay et al., 2014). Lack of OX40:OX40L signaling resulted in decreased IFNγ and auto-Ab production, and increased tissue integrity in CIA (Gwyer Findlay et al., 2014; Yoshioka et al., 2000). Furthermore, GITR (TNFRSF18, CD357) promoted production of proinflammatory cytokines and chemokines (Cuzzocrea et al., 2005), while blocking the CD27:CD70 pathway ameliorated arthritis by repressing autoAb production (Oflazoglu et al., 2009). In contrast, a 4-1BB agonist Ab substantially ameliorated established arthritis by induction of tolerogenic DCs and subsequent induction of regulatory CD8+ cells (Seo et al., 2004). Thus, while most TNFRSF co-stimulatory pathways promote RA, some may protect. Also, co-stimulation not only affects T cell function but also impacts APCs that express the corresponding ligands.
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While co-stimulatory signals are exacerbated in RA, defects of co-inhibitory pathways are also implicated in the susceptibility to, and progression of, RA. Polymorphisms within the CTLA4 locus have been described in subgroups of RA patients (Saverino et al., 2010). Treg cells from active RA patients had increased methylation at the CTLA4 promoter, which led to reduction in CTLA4 expression and failure to activate the tolerogenic indoleamine 2,3dioxygenase pathway (Cribbs et al., 2014). These findings raise the possibility that intrinsic defects of co-inhibition contribute to the systemic loss of tolerance in RA.
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Defects in the PD1 co-inhibitory pathway have also been implicated in RA pathogenesis. Polymorphisms within the PDCD1 locus appear to be associated with RA (Okazaki and Honjo, 2007), while soluble PD1 correlated with increased TNFα levels in RA patients (Wan et al., 2006). Curiously, serum levels of auto-Abs against PD-L1 were found to correlate with active disease in RA patients (Dong et al., 2003), although their functional significance needs to be evaluated further. Pdcd1−/− mice were more susceptible to CIA, whereas activation of the PD1 co-inhibitory pathway by PD-L1.Fc ameliorated disease via reduced IFNγ production (Raptopoulou et al., 2010), suggesting that sufficient PD1 coinhibition is required to control the development of CIA. The role of additional IgSF co-inhibitory receptors in RA has been studied recently. TIGIT (VSIG9, VSTM3) shares the same ligands CD112 and CD155 with another co-stimulatory
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receptor CD226, and exerts suppressive effects on T cell activation and function in CIA (Levin et al., 2011). Another B7 family co-inhibitory receptor, B7-H3 (CD276), is expressed on B7.1−B7.2− fibroblast-like synoviocytes from RA patients (Tran et al., 2008). However, B7-H3 seems to transduce co-stimulatory signals in Th1 and Th17 cells as Cd276−/− mice were more resistant to CIA with decreased IL6, IL17 and TNFα levels (Luo et al., 2015). Studies with the inhibitory ligands HVEM (TNFRSF14, CD270) and Galectin9 have impacted a role for their respective co-inhibitory receptors BTLA and TIM3 (HAVCR2, CD366) in RA pathogenesis. Treatment with HVEMIg augmented CIA (Pierer et al., 2009), raising the possibility that BTLA may impact RA. Galectin 9-deficient mice were more susceptible to CIA induction, while treatment with Galectin 9 ameliorated the disease severity (Seki et al., 2008), implicating a role for TIM3. However, the complexity of these pathways and the paucity of studies on the role of co-inhibitory pathways in RA has limited our understanding of how these pathways might be manipulated therapeutically.
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While Abatacept has proven to be an effective treatment for RA, it is clear that additional therapies, used in combination, will be required for complete resolution of the disease in all RA patients. In contrast, a protective role of co-inhibitory pathways has also been demonstrated in RA (Figure 2). Although intrinsic defects in these pathways that appear to be associated with susceptibility to RA have been suggested, a clearer understanding of their importance and relevance is needed. As with other autoimmune diseases, it remains to be seen whether boosting coinhibition is a viable therapeutic strategy for RA.
Multiple Sclerosis Author Manuscript
Multiple Sclerosis (MS) is an autoimmune disorder characterized by immune cell infiltration and inflammation within the brain and spinal cord (central nervous system, CNS) that leads to progressive demyelination and neurodegeneration (Dendrou et al., 2015). Macrophages, autoreactive CD8+ T cells, Th1 and Th17 cells and clonally expanded B cells dominate the infiltrate across the blood-brain barrier. The myelin sheaths that surround nerves in the CNS contain myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), proteolipid protein (PLP), myelin-associated glycoprotein (MAG), and 2′,3′-CNP. Auto-Abs and autoreactive T cells against these auto-Ags have been identified in MS patients. CNSresident cells, microglia and astrocytes are activated during the inflammatory process and also produce proinflammatory mediators, exacerbating the disease.
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Numerous murine experimental autoimmune encephalomyelitis (EAE) models have provided insightful understanding of MS etiology (Dendrou et al., 2015). Models discussed here include: (a) PLP139-151-immunized SJL/J mice, MOG35-55-immunized C57BL/6J mice or MBP-immunized PLxSJL F1 mice, which exhibit and a chronic EAE course; (b) PLP139-151-immunized SJL/J mice, in which epitope spreading occurs with a relapsingremitting disease course (R-EAE); and (c) MBP-reactive TCR or MOG-reactive TCR (2D2) transgenic mice that exhibit a spontaneous chronic EAE disease course. In these EAE models, IFNγ and IL17 produced by Th1 and Th17 cells, respectively, are dominant
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proinflammatory factors, while GM-CSF production by a subset of pathogenic Th17 cells promotes chronic encephalomyelitis (Dendrou et al., 2015).
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Several co-stimulatory pathways have been studied using these EAE models. The CD28:B7 co-stimulatory pathway was found to be essential in lowering the threshold for autoreactive T cell priming during the development of encephalomyelitis. Spontaneous development of EAE was abrogated in Cd28−/− MBP1-17 TCR transgenic mice, but could be reversed by high doses of MBP (Oliveira-dos-Santos et al., 1999). Likewise, C57BL/6J mice lacking both B7.1 and B7.2 were completely resistant to MOG35-55-induced EAE (Chang et al., 1999). However, blockade or deficiency of both B7.1 and B7.2 exacerbated EAE on an SJL/J background (Jabs et al., 2002; Perrin et al., 1996b; Racke et al., 1995), suggesting that the requirement of B7.1 and B7.2 for EAE induction appears to be influenced by the mouse genetic background (Jabs et al., 2002). The contribution of B7.1 and B7.2 is also timedependent as the impact of CD28:B7 blockade on EAE severity is affected by the time and dosage of CTLA4Ig administration (Khoury et al., 1995; Perrin et al., 1996b; Racke et al., 1995; Vogel et al., 2015). B7.1 and B7.2 are dynamically expressed on different cell types during different phases of EAE, and the presentation of myelin epitopes is largely B7.1dependent (Cross et al., 1999; Karandikar et al., 1998; Miller et al., 1995), indicating that co-stimulation via B7.1 might be more dominant in promoting EAE. While blocking with anti-B7.2 had minimal effect, blocking with anti-B7.1 reduced disease severity in both chronic EAE and R-EAE models (Kuchroo et al., 1995; Miller et al., 1995; Perrin et al., 1996b; Racke et al., 1995). However, B7.1 or B7.2 single knockout C57BL/6J mice developed similar disease severity as wild-type mice in the MOG35-55-induced EAE model (Chang et al., 1999), suggesting that B7.1 and B7.2 may function redundantly. Despite uncertainties about the efficacy of CTLA4Ig in mouse EAE models, Abatacept therapy has shown some efficacy in clinical trials and appears to limit MBP-reactive T cells (Viglietta et al., 2008). In contrast, a human CD28 blocking Ab prevented CNS pathology in human MOG-induced EAE in rhesus monkeys (Haanstra et al., 2015), indicating selective blockade of CD28 might be another option to inhibit autoreactive T cell activation.
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Unlike the co-stimulatory receptor CD28 or the role of ICOS in other autoimmune diseases, ICOS exerts a differential impact during the priming and efferent phases in EAE models. Selective ICOS blockade during the priming phase [1–10 days after immunization] exacerbated disease, whereas selective blockade during the efferent phase [9–20 days after immunization] ameliorated disease (Sporici et al., 2001). Likewise, ICOS blockade promoted effector 2D2 T cell-induced EAE, but mitigated memory 2D2 T cell-induced EAE (Elyaman et al., 2008). Interestingly, Icos−/− mice develop more severe EAE with enhanced Th1 and Th17 cell cytokine production, possibly due to the reduced IL4 and IL10 production that limits Th1 and Th17 cell priming (Dong et al., 2001; Galicia et al., 2009). It has been suggested that CD28-mediated T cell priming is dependent on B7 upregulation on APCs via CD40:CD40L co-stimulation (Yang and Wilson, 1996). Indeed, EAE could not be induced in Cd154−/− mice unless B7 was overexpressed on APCs (Grewal et al., 1996). CD40 is expressed in the CNS of MOG-induced EAE mice as well as active lesions of MS patients (Becher et al., 2001; Gerritse et al., 1996). Treatment with CD40L Ab completely prevented the development of EAE, and also reduced clinical severity in mice with
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established EAE by suppressing T cell activation and IFNγ production (Gerritse et al., 1996; Howard et al., 1999). Preclinical assessment of anti-CD40 in monkeys also provided support for its therapeutic potential in the treatment of MS (Boon et al., 2001; Boon et al., 2002; Laman et al., 2002), but human trials were halted due to unanticipated thromboembolic complications (Ford et al., 2014).
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Additional co-stimulatory pathways appear to complement CD28:B7 co-stimulation in promoting MS pathogenesis. For instance, expansion of MBP-reactive T cells from MS patients was CD28:B7 co-stimulation-independent (Scholz et al., 1998), while double immunization reversed the protection against EAE in Cd28−/− mice (Chitnis et al., 2001). Interestingly, OX40L blockade ameliorated EAE in double immunized Cd28−/− mice (Chitnis et al., 2001). OX40 is up-regulated on autoreactive T cells within active lesions in both EAE mice and MS patients, and anti-OX40:toxin conjugate-mediated depletion of OX40+ T cells reduced EAE (Carboni et al., 2003; Weinberg et al., 1996). The OX40:OX40L co-stimulation axis mediates autoreactive T cell priming, migration and function in EAE (Ndhlovu et al., 2001; Nohara et al., 2001; Weinberg et al., 1999). However, this axis does not appear to be a primary co-stimulatory pathway promoting EAE as deficiency in either OX40 or OX40L, or blockade of OX40:OX40L interactions led to a reduction of, but not complete protection against, EAE (Carboni et al., 2003; Ndhlovu et al., 2001; Nohara et al., 2001; Weinberg et al., 1999). In addition, transgenic mice overexpressing OX40L developed enhanced EAE, but were protected against EAE in the absence of CD28 or CD40 (Ndhlovu et al., 2001), suggesting a prerequisite for the CD28:B7 or CD40:CD40L co-stimulatory pathways in OX40-mediated autoreactive T cell priming.
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The role of other TNFRSF co-stimulatory receptors has also been studied in EAE. Deficiency of 4-1BB ligand (TNFSF9, CD137L) resulted in resistance to MOG35-55-induced EAE, reduction in Th1 and Th17 cell cytokine production and autoreactive T cell infiltration (Martinez Gomez et al., 2012). However, agonistic 4-1BB Abs ameliorated disease severity in MOG35-55 induced EAE mice by promoting activation-induced cell death of autoreactive T cells and inhibiting Th17 cell differentiation (Kim et al., 2011; Sun et al., 2002b). Thus, negated or exacerbated 4-1BB signaling limits EAE, suggesting that a defined, optimal window of 4-1BB co-stimulation is required to promote EAE.
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Analysis of the impact of the CD27:CD70 co-stimulation axis in EAE has added more complexity. While CD70 blockade inhibited EAE induction in PLP139-151-immunized SJL/J mice by repressing TNFα production (Nakajima et al., 22000), MOG35-55-induced EAE was exacerbated in Cd27−/− or Cd70−/− mice and ameliorated in transgenic mice overexpressing CD70, where IL17 and CXCR6 expression was suppressed in differentiating Th17 cells (Coquet et al., 2013). These studies provide another example of a co-stimulatory pathway that seems to have a differential impact depending on the type of EAE model and/or mouse genetic backgrounds. While aberrant co-stimulation leads to MS pathogenesis, insufficient co-inhibition can also promote the development and progression of MS as is seen in other autoimmune diseases. The co-inhibitory receptor CTLA4 was found to be dysregulated in MBP-reactive T cells from MS patients compared with healthy controls (Oliveira et al., 2003). CTLA4 blockade
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resulted in exacerbated EAE, increased cytokine production, and enhanced epitope spreading (Hurwitz et al., 1997; Karandikar et al., 2000; Karandikar et al., 1996; Perrin et al., 1996a). Lack of CTLA4 co-inhibition also induced severe disease in EAE-resistant BALB/c mice (Hurwitz et al., 2002), highlighting a key role for CTLA4 in limiting selfreactivity and preventing EAE development. However, a recent study suggests that CTLA4 may also intrinsically limit Treg cell activation and expansion, and deletion of Ctla4 in Treg cells during adulthood was necessary and sufficient to provide protection from EAE (Paterson et al., 2015). CTLA4 appeared to negatively select Treg cells and narrow the conventional T cell repertoire by restricting TCRα chain usage in an MBP-reactive Vβ8.2 transgenic model, and therefore these transgenic mice were protected from spontaneous EAE in the absence of CTLA4 expression in the thymus (Verhagen et al., 2009; Verhagen et al., 2013). These studies highlight the differential impact of CTLA4 co-inhibition in the thymus versus the periphery, as well as its inhibitory effect on both autoreactive T cells and Treg cells.
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Other inhibitory receptors also limit MS and EAE. Polymorphisms in the PDCD1 locus appear to be associated with disease progression in MS patients (Okazaki and Honjo, 2007), while Pdcd1−/− mice are more susceptible to MOG35-55-induced EAE (Carter et al., 2007). PD1 and its ligands PD-L1 and PD-L2 are expressed on CNS-infiltrating cells, and PD-L1 but not PD-L2 is substantially upregulated on endothelium and microglial in the CNS of EAE mice and MS patients (Liang et al., 2003; Magnus et al., 2005; Schreiner et al., 2008). Consistent with these observations, PD-L1 plays a more critical role than PD-L2 in controlling EAE as demonstrated using Cd274−/− versus Cd273−/− mice, respectively (Bodhankar et al., 2013; Carter et al., 2007; Latchman et al., 2004; Schreiner et al., 2008). However, it is notable that the relative contribution of PD-L1 and PD-L2 in controlling EAE varies in different mouse strains and may also depend on the phase of disease (Zhu et al., 2006). Interestingly, B7.1 has been identified as another ligand for PD-L1, and interactions between B7.1 and PD-L1 inhibit T cell responses (Butte et al., 2007). The differential role of B7.1 and B7.2, and PD-L1 and PD-L2 observed in different mouse strains may reflect a preferential usage of the B7.1:PD-L1 axis in certain strains.
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Newly identified IgSF co-inhibitory receptors have also been implicated in modulating the disease course of MS. While transgenic mice overexpressing TIGIT or mice activated by a TIGIT agonist Ab showed reduced EAE symptoms, Tigit−/− mice were more susceptible to EAE (Joller et al., 2011; Levin et al., 2011). TIGIT cell-intrinsically suppressed T cell activation and function in the 2D2 TCR transgenic mouse model (Joller et al., 2011). The expression of another co-inhibitory receptor, TIM3 was found to be impaired in MS patients (Koguchi et al., 2006; Yang et al., 2008). Interaction between TIM3 and its ligand Galectin-9 negatively regulates Th1 cell responses in PLP139-151-immunized SJL/J mice (Monney et al., 2002; Sabatos et al., 2003; Zhu et al., 2005). While blockade of B7-H4, another B7 family co-inhibitory receptor, exacerbated EAE disease, activation of its unidentified ligand on T cells by B7-H4Ig provided protection against EAE (Podojil et al., 2013; Prasad et al., 2003). Btla−/− T cells showed increased proliferation and mediated attenuated EAE (Watanabe et al., 2003), suggesting that BTLA may also regulate autoreactive T cells. However, the role of B7-H3 in MOG35-55-induced EAE seems controversial. B7-H3 blockade resulted in enhanced EAE, whereas mice deficient in B7-H3 showed reduced disease severity and Th1 Immunity. Author manuscript; available in PMC 2017 May 17.
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and Th17 cell cytokine production (Luo et al., 2015; Prasad et al., 2004), suggesting that more analysis of this pathway is required. Collectively, these studies suggest that multiple co-inhibitory receptors can limit EAE inferring that boosting co-inhibitory signals might be a valid therapeutic approach for MS. T cells contribute a critical and central role in the pathogenesis and progression of EAE and MS. Consequently, there are multiple co-stimulatory and co-inhibitory receptors that impact disease and thus offer opportunities for therapeutic intervention (Figure 3). Interestingly, the role of several co-stimulatory and co-inhibitory receptors (B7.1 and B7.2, CD27 and CD70, and PD-L1 and PD-L2) appears to be affected by the EAE model and/or the genetic background used. Whether this reflects subtle nuances between these different model systems or a potential heterogeneous outcome in targeting these pathways in MS patients remains to be determined.
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Type 1 Diabetes Type 1 Diabetes (T1D), also referred as Juvenile Diabetes, is a chronic autoimmune disorder associated with the destruction of insulin-secreting β-cells by autoreactive T cells and subsequent uncontrolled hyperglycemia (Atkinson et al., 2014). Around 60 T1Dsusceptibility regions have been mapped thus far, with the strongest association (HLA locus) and several additional prominent associations (eg. PTPN22, CTLA4, IL2RA) impacting T cell activation. Although multiple immune cell types participate in this disease, autoreactive CD4+ and CD8+ T cells are key drivers in the propagation of T1D, while Treg cells limit diabetogenic T cell function (Herold et al., 2013).
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The non-obese diabetic (NOD) mouse is the T1D model of choice for the analysis of immune mechanisms that modulate the onset and progression of autoimmune diabetes (Reed and Herold, 2015). Autoimmune diabetes in NOD mice shares various common features with T1D in humans. NOD mice spontaneously develop chronic autoimmune diabetes, with insulitis starting at 3–4 weeks-of-age and subsequent diabetes onset occurring between 12– 25 weeks-of-age in female mice, while male NOD mice exhibit reduced onset and incidence. Similarly, various insulin-dependent diabetes susceptibility regions (Idd) have also been mapped in NOD mice. Variants of this model include the adoptive transfer of diabetic NOD splenocytes or islet-Ag specific TCR transgenic T cells (eg. BDC2.5) into NOD.scid mice.
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Several co-stimulatory receptors have been shown to be critical for the development of autoimmune diabetes in NOD mice. Even though the CD28:B7 axis provides essential costimulation for autoreactive T cell priming, unlike other autoimmune diseases discussed above, it is also critical for Treg cell development and homeostasis in autoimmune diabetes. Both Cd28−/− and B7.1-B7.2 double-deficient NOD mice had a profoundly reduced number of CD4+CD25+ Treg cells, and thus exhibited accelerated autoimmune diabetes (Salomon et al., 2000). In addition, defects in CD27:B7 co-stimulation broke the Th1-Th2 balance with enhanced IFNγ production in NOD mice (Lenschow et al., 1996). The protective effect of CD28:B7 co-stimulation seems to be mainly provided by B7.1 as blocking both B7.1 and B7.2 or blocking B7.1 alone in NOD mice had a similar effect (Lenschow et al., 1995), while the phenotype in B7.1-deficient versus B7.1-B7.2-double deficient NOD mice appears
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comparable (Salomon et al., 2000). However, B7.2-deficient NOD mice were free of autoimmune diabetes (Bour-Jordan et al., 2004), and treatment of young NOD mice (2 week-of-age) with anti-B7.2 resulted in delayed diabetes onset as well as reduced insulitis and T cell activation, but the protective effect that was abolished if anti-B7.2 was administrated in older NOD mice (Lenschow et al., 1995). Thus, B7.1 and B7.2 may have different functions depending on the timing and context of their involvement (Butte et al., 2007; Paterson et al., 2011). NOD mice ectopically expressing CTLA4Ig or treated with murine CTLA4Ig at 2–4 weeks-of-age lacked CD4+CD25+ Treg cells and exhibited exacerbated autoimmune diabetes, consistent with observations in Cd28−/− NOD mice (Lenschow et al., 1996; Salomon et al., 2000). Despite this unexpected phenotype in NOD mice, Abatacept (human CTLA4Ig) treatment showed some efficacy in recent-onset T1D patients, with ~9.5 month delay in C-peptide decline and lower levels of HbA1c compared to the placebo group (Orban et al., 2014). Nevertheless, the generally limited impact of Abatacept suggested that other co-stimulatory pathways independent of the CD28:B7 axis are involved in T1D pathogenesis.
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ICOS:ICOSL co-stimulation is also exploited by both autoreactive T cells and Treg cells in autoimmune diabetes. Blockade with anti-ICOS resulted in delayed autoimmune diabetes in NOD mice, and Icos−/− NOD mice were free of autoimmune diabetes with reduced IFNγ production (Ansari et al., 2008; Hawiger et al., 2008). Conversely, other studies using the BDC2.5 TCR transgenic NOD model demonstrated that ICOS is preferentially expressed on Treg cells and mediates enhanced suppressive capacity of Treg cells (Herman et al., 2004; Kornete et al., 2015; Kornete et al., 2012), with ICOS blockade in BDC2.5 NOD mice resulting in rapid diabetes onset (Ansari et al., 2008; Herman et al., 2004). Thus, in contrast to the role of ICOS in other autoimmune diseases, the impact of ICOS blockade depends on the model used and its differential impact on diabetogenic T cells versus Treg cells.
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Unlike the CD28:B7.1 and ICOS:ICOSL co-stimulatory pathways that are important for both autoreactive T cell activation and Treg cell homeostasis, the CD40:CD40L axis appears to have less impact on Treg cells in autoimmune diabetes. CD40:CD40L co-stimulation is required for the initiation of insulitis and autoreactive T cell priming in autoimmune diabetes, which also differs from its canonical role in activating APCs and/or humoral immunity in other autoimmune diseases. Blockade with anti-CD40L in neonates or deficiency of CD40L prevented autoimmune diabetes in NOD mice (Baker et al., 2008; Balasa et al., 1997; Bour-Jordan et al., 2004; Green et al., 2000). Cd154−/− autoreactive CD4+ T cells appeared to lose their diabetogenic potential even though APCs were systemically activated through CD40 ligation (Amrani et al., 2002), suggesting that either CD40L is essential for diabetogenic T cell activation or there may be another receptor for CD40L that activates APCs. In contrast to the CD40:CD40L axis, OX40:OX40L co-stimulation appears to be more important at later stages of autoimmune diabetes. OX40 is expressed on primed (CD44hi) T cells and OX40L (encoded by Tnfsf4) is upregulated on DCs after insulitis initiation but prior to islet destruction (11–13 week-of-age). Thus, interruption of OX40:OX40L interactions had no effect on diabetes onset in young NOD mice but exhibited the most significant delay in diabetes onset in NOD mice at 12 week-of-age (Pakala et al., 2004).
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Interestingly, Tnfsf4−/− NOD mice exhibited normal (or even accelerated) insulitis but did not develop autoimmune diabetes (Martin-Orozco et al., 2003), supporting the idea that different co-stimulatory axes participate at different stages to promote autoimmune diabetes.
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Another TNFRSF member, 4-1BB (TNFRSF9), has also been studied in autoimmune diabetes. Tnfrsf9 has been mapped to Idd9.3, which mediates susceptibility to autoimmune diabetes in NOD mice. However, the autoimmune diabetes-resistant NOD.B10 Idd9.3 locus facilitates enhanced Treg cell induction and secretion of soluble 4-1BB that blocks the 4-1BB co-stimulatory signal on autoreactive T cells (Cannons et al., 2005; Kachapati et al., 2012; Lyons et al., 2000). Interestingly, while treatment with 4-1BB agonist Ab prevented autoimmune diabetes in NOD mice by inducing Treg cells, overexpression of a 4-1BB agonist induced severe autoimmune diabetes (Irie et al., 2007; Kachapati et al., 2013; Sytwu et al., 2003). 4-1BB is constitutively expressed on Treg cells, but transiently upregulated on effector T cells after activation. Therefore, there might be functionally and/or temporally distinct usage of 4-1BB on Treg cells versus autoreactive T cells in autoimmune diabetes. Collectively, these studies highlight the importance of multiple co-stimulatory receptors in modulating autoimmune diabetes via their differential impact on diabetogenic T cell function and Treg cell homeostasis.
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In addition to Treg cell-mediated suppression, co-inhibitory receptors also provide cell intrinsic regulation of autoreactive T cells in NOD mice. For instance, CTLA4 is critical for controlling autoimmune diabetes. Polymorphisms within the CTLA4 locus have been identified that appear to associate with susceptibility to T1D and map to Idd5.1 in NOD mice (Saverino et al., 2010; Wicker et al., 2004). NOD mice are genetically deficient in expression of a CTLA4 splice variant that cannot bind to its B7 ligand (ligand-independent CTLA4; li-CTLA4) (Ueda et al., 2003; Vijayakrishnan et al., 2004). Curiously, restoration of li-CTLA4 expression in NOD mice limits insulitis and autoimmune diabetes in full-length CTLA4-dependent manner (Araki et al., 2009; Stumpf et al., 2013). Genetic deletion or blockade of CTLA4 showed dramatic acceleration of diabetes onset in NOD mice (Luhder et al., 2000; Luhder et al., 1998), whereas APC-directed CTLA4 engagement delayed autoimmune diabetes onset by inhibition of B cell maturation (Fife et al., 2006). CTLA4 engagement dampens diabetogenic T cell activity but in a very restricted time window that coincides with islet Ag re-encounter (Luhder et al., 2000; Luhder et al., 1998). Interestingly, CTLA4 upregulation is prevented by low CD86 expression and impaired T cell priming in NOD mice (Dahlen et al., 2000), suggesting that optimal T cell priming is also required to induce cell-intrinsic negative signals.
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PD1:PD-L1 or :PD-2 interactions mediate co-inhibitory effects that appear to be distinct from CTLA4. Polymorphisms at the PDCD1 locus are associated with susceptibility to T1D (Okazaki and Honjo, 2007). Pdcd1−/− NOD mice developed autoimmune diabetes by 11 weeks-of-age with 100% penetrance in both females and males (Wang et al., 2005). In contrast to CTLA4 blockade, treatment with anti-PD1 or anti-PD-L1, but not anti-PD-L2, precipitated insulitis and autoimmune diabetes onset in NOD mice regardless of when the mice are treated [1–10 weeks-of-age] (Ansari et al., 2003), suggesting PD1:PD-L1 interactions impact all stages of autoimmune diabetes onset and progression. PD1 appears to prevent stable interactions between T cells and DCs in pancreatic lymph nodes (Fife et al.,
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2009). Interestingly, PD-L1 may also be expressed on pancreatic islets (Ansari et al., 2003; Liang et al., 2003), providing a regulatory signal before autoreactive T cells enter the islets. Interaction between PD-L1 and another of its known ligands B7.1 induces negative signals in diabetogenic T cells at the late phase of autoimmune diabetes (Paterson et al., 2011). Curiously, while PD-L1 overexpression on β-cells exhibited a protective role in NOD mice (Wang et al., 2008), its overexpression on β-cells in B6 mice provoked autoreactive T cells (Subudhi et al., 2004). The basis for these contradictory observations remains to be defined. Besides its regulation on peripheral autoreactive T cells, it is noteworthy that PD1 may also impacts thymic selection of diabetogenic T cells (Zucchelli et al., 2005).
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Like PD1, the inhibitory receptor LAG3 (CD223) is also required to restrain the expansion of diabetogenic T cells in the islets at both early and late stages of autoimmune diabetes. LAG3 is a hom*olog to CD4 that also binds to MHC class II molecules, but with a higher affinity, and utilizes a unique, conserved intracellular KIEELE motif to mediate its regulatory function (Workman et al., 2002). Both female and male Lag3−/− NOD mice develop accelerated autoimmune diabetes with 100% penetrance and exhibit increased accumulation of islet Ag-specific T cells in the islets (Bettini et al., 2011). LAG3 blockade after the initiation of insulitis also precipitated diabetes onset (Bettini et al., 2011), synonymous with PD1 blockade but distinct from CTLA4 blockade. Interestingly, LAG3 is highly upregulated on CD4+CD25+ Treg cells and appears to mediate their suppressive function (Huang et al., 2004; Liang et al., 2008). This raises the possibility that the exacerbated autoimmune diabetes observed in Lag3−/− NOD mice is partially due to impaired Treg cell suppression in the absence of LAG3.
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Co-inhibitory receptors TIM3 and B7-H4 may also play a role in dampening β-cell destruction at this later stage. Treatment with either anti-TIM3 or TIM3Ig that blocks interactions between endogenous TIM3 and its ligand augmented autoimmune diabetes but did not impact insulitis (Sanchez-Fueyo et al., 2003). Likewise, early treatment with B7H4Ig that provides co-inhibitory signals via its unknown ligand on T cells did not block insulitis but delayed aggressive β-cell destruction at the later stage (Wang et al., 2011). Thus, the analysis of co-inhibitory receptors in NOD mice suggests that these pathways are broadly utilized but at different stages during the pathogenesis of autoimmune diabetes.
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The most prominent feature of co-stimulatory or co-inhibitory pathway utilization in autoimmune diabetes is the differential temporal utilization observed. CD28:B7 and CD40:CD40L costimulation, and CTLA4-mediated inhibition appear to be more important during disease onset and establishment of insulitis. In contrast, other co-stimulatory and coinhibitory receptors are utilized more broadly or at later stages of disease progression after insulitis onset (Figure 4). In addition, co-stimulation is also essential for the maintenance of Treg homeostasis in NOD mice, potentially complicating the therapeutic potential of some modalities.
Hierarchical usage of co-stimulatory and co-inhibitory pathways It is clear from the four disease-focused sections above that a wide variety of co-stimulatory and co-inhibitory pathways impact and shape systemic and organ-specific autoimmune
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disease. This evaluation not only provides an opportunity to compare and contrast their utilization in four distinct but nevertheless emblematic autoimmune diseases, but also offers potential approaches to address some unanswered questions. What appears to be clear feature is the hierarchical utilization of both co-stimulatory and coinhibitory pathways (Figure 1–4). This notion is highlighted by six general observations.
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First, there are “first-line” and “second-line” pathways impacting autoimmune disease. The CD28 co-stimulation is a “first-line” pathway essential for autoreactive T cell priming, whereas PD1 has a dominant “first-line” inhibitory impact on all autoimmune disease models discussed. However, the relative contributions of their ligands B7.1, B7.2 and PDL1, PD-L2, respectively, seem to be affected by the genetic background, and occasionally, the model system used, which may be explained by the timing of ligand expression and interaction, cell types that preferentially express one ligand versus the other, and/or the addition of B7.1:PD-L1 interactions in different mouse strains or models. This is probably further complicated by differential interactions between B7 molecules with CTLA4, as a lack of CTLA4 co-inhibition precipitates autoimmune manifestations under autoimmuneprone conditions, albeit to differing degrees. Studies with Abs that specifically block CD28:B7.1, CD28:B7.2, CTLA4:B7.1, CTLA4:B7.2, PD1:PD-L1, PD1:PD-L2 and PDL1:B7.1 interactions would help to clarify the relative contribution of these receptors and ligands. There may also be “second-line” pathways that do not impact all autoimmune disease all the time. For instance, while many IgSF co-inhibitory receptors are upregulated on autoreactive T cells and reinforce co-inhibitory signals after T cell priming, their contribution may not impact all autoimmune diseases equally. Inhibitory receptors such as LAG3, TIM3, TIGIT, BTLA4, B7-H3 and B7-H4 are either not consistently utilized between diseases or they need to be studied further to fully assess their true impact. Second, there are also temporal implications in the use of different co-stimulatory and coinhibitory pathways. For instance unlike the CD28:B7 or CD40:CD40L axes, the other TNFRSF co-stimulatory pathways tend to participate at later stages, probably because these receptors are upregulated on activated T cells and/or their corresponding ligands may be restricted to inflamed tissues. From studies in autoimmune diabetes, it would appear that CTLA4 functions in a more restricted time window during the priming phase, while TIM3 and B7-H4 play a role in the later stage. This contrasts with PD1 and LAG3 that appear to be involved over a broader time period. Whether this applies to other autoimmune diseases remains to be determined.
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Third, while there is differential usage of each co-stimulatory pathway, compensatory mechanisms also exist when some co-stimulatory pathways are absent to promote T and B cell self-reactivity. For instance, CD28:B7.1 but not CD28:B7.2 co-stimulation predominantly provides T cell priming signals, but blockade of B7.1 alone does not always result in significant reduction in disease severity, especially in systemic autoimmune diseases (eg. SLE, RA). The loss of CD28:B7.1 co-stimulation can be compensated for by either increased utilization of CD28:B7.2 co-stimulation and/or exploiting the use of other receptor-mediated co-stimulation, such as the CD40:CD40L, ICOS:ICOSL and
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OX40:OX40L axes. Therefore, combinatorial blocking approaches could be exploited to enhance efficacy. Fourth, while TNFRSF co-stimulatory pathways predominantly promote T cell selfreactivity, they do not do so uniformly or to the same extent and occasionally exhibit an unexpected regulatory capacity. For instance, the OX40:OX40L pathway promotes all four autoimmune diseases to some extent, while the CD27:CD70 and GITR:GITRL pathways contribute to a variable degree. Interestingly, in some settings the 4-1BB:4-1BBL pathway can promote or inhibit immunity. For instance, the co-stimulation of 4-1BB via its endogenous ligand 4-1BBL can provide stimulatory signals, but agonist 4-1BB Abs promote activation-induced cell death and/or the generation of tolerogenic DCs or Treg cells in multiple autoimmune settings. Determining whether there are any other unknown binding partners may help to clarify some of these ambiguities.
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Fifth, the utilization of specific co-stimulatory and co-inhibitory axes is likely impacted by the cellular mechanisms that promote pathology in each disease. For instance, TIM3 is preferentially expressed on Th1 cells, so it may have more impact on Th1-mediated autoimmune diseases (eg. MS, T1D). Conversely, both the CD40:CD40L and the ICOS:ICOSL axes facilitate crosstalk between autoreactive T and B cells, but to differing extents. CD40:CD40L co-stimulation promotes B cell activation, maturation and upregulation of B7 molecules, and thus provides strong signals for T cell activation via the CD28:B7 axis. Therefore, CD40:CD40L co-stimulation is required to initiate the development of autoimmune diseases. However, ICOS:ICOSL co-stimulation is required for the generation, function and maintenance of Tfh cells that help GC formation and auto-Ab production. Therefore, the ICOS:ICOSL axis has a greater impact on systemic autoimmune disorders that are dominated by thymus-dependent humoral immune responses. Likewise, the SLAMF receptors affect Tfh cell development and function, so thus appear to have a greater role in IC-mediated autoimmune diseases (eg. SLE).
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Sixth, while co-stimulation is essential to prime autoreactive T cells and sustain their selfreactivity, it is also critical for the maintenance of Treg cell homeostasis and function, as is demonstrated in autoimmune diabetes, which further complicates data interpretation and a full understanding of their role in shaping autoimmune disease. For instance, while it is clear that CD28 provides a dominant co-stimulatory contribution in promoting autoimmunity, it can also impact Treg cell development and thereby limit autoimmunity. Also, while coinhibitory receptors are highly upregulated on Treg cells, it is unclear whether they mediate the cell-intrinsic regulation of Treg cell function or the cell-extrinsic Treg cell-mediated control of autoreactive T cells. Studies with cell type-restricted deletion of co-inhibitory molecules may help to clarify their roles and define populations that could be targeted therapeutically.
Concluding remarks Although remarkable progress has been made in the past few decades in defining how costimulatory and co-inhibitory pathways impact autoimmune diseases, many questions and challenges still remained. Four are particularly noteworthy.
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First, what additional co-stimulatory and co-inhibitory pathways impact autoimmune disease? It is evident from the discussion above that there remain gaps in our understanding of the role of certain co-stimulatory and co-inhibitory receptors and ligands in many autoimmune diseases. Filling in these gaps will provide a greater appreciation for the global impact of each pathway. Although this review only focused on four autoimmune diseases, it is clear that expanding this sphere of knowledge to all autoimmune disease would be highly valuable, and will be essential for shaping future therapeutic strategy. We should also not rule out the possibility that there are additional co-stimulatory and co-inhibitory receptors and ligands that remain to be discovered or novel receptors/ligands for known molecules. Indeed, the receptor for B7-H4 remain elusive and we have yet to fully understand the impact of more recently discovered B7 family co-modulatory molecules VISTA (B7-H5, Gi24, Dies1), B7-H6 and B7-H7 .
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Second, can effective therapeutic strategies be developed for the treatment of autoimmune disease by modulating co-stimulatory and co-inhibitory pathways? The impact of blocking the inhibitory receptors CTLA4 and PD1 in the treatment of cancer has been spectacular, with justifiable excitement about the potential for a long pipeline of blocking and agonist Abs that are in early stage trials or in development (Topalian et al., 2015). The key challenge is whether the same therapeutic impact can be achieved for autoimmune diseases by modulating co-stimulatory and coinhibitory pathways? This is likely to be a greater challenge and will inevitably require a combinatorial approach that effectively block co-stimulatory pathways while enhancing coinhibition. Indeed, in light of the redundant use of many co-stimulatory pathways and the inadequacy of host co-inhibitory signals to suppress autoreactive T and B cells, modulating a single or even multiple pathways is not likely to be sufficient.
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Third, how can we minimize the adverse side effects of targeting co-stimulatory pathways in patients with autoimmune disease? As autoimmune disease tends not to be immediately life threatening, unlike cancer, the risk tolerance in therapeutic development is lower. Thus an additional challenge to the one cited above is to also ensure that therapies have relatively high safety profile. For instance, blocking CD40:CD40L co-stimulation exhibited some efficacy in earlier preclinical and clinical trials for autoimmune disease, but have been halted due reported adverse thromboembolic events (Ford et al., 2014). While this creates unique challenges for the treatment of systemic autoimmune diseases, it might be feasible to target specific tissues, and thus organ specific autoimmune diseases, using targeted therapies such as engineered viral vector or nanoparticle delivery of co-stimulatory or co-inhibitory modulators.
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Fourth, what immune cell population should be targeted? Many of the co-stimulatory and co-inhibitory pathways discussed above impact both the pathogenic effector and regulatory populations. Thus the global targeting of any pathway can have mixed and/or unexpected outcomes. This raises the question of whether it will be possible to develop therapies that target specific cell types. Given the significant impact of co-stimulatory and co-inhibitory pathways in autoimmunity, there is clearly significant justification and momentum to expand our understanding, and
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determine the full impact of, these pathways in all autoimmune diseases. While the development of effective therapies for autoimmune diseases remains a major challenge, the impact of targeting these pathways in cancer should serve as a source of encouragement.
Acknowledgments The authors wish to thank the Vignali Lab helpful discussions. This work was supported by the National Institutes of Health (AI108545, AI091977 and DK089125 to D.A.A.V), and the NCI Comprehensive Cancer Center Support CORE grant (CA047904, to D.A.A.V.).
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Author Manuscript Author Manuscript Figure 1. Co-stimulatory and co-inhibitory pathways in Systemic Lupus Erythematosus (SLE)
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The hierarchical utilization of co-stimulatory and co-inhibitory receptors and their corresponding ligands is compared in SLE. The extent to which a co-stimulatory or coinhibitory molecule is utilized is indicted by dark (dominant utilization - red or blue) or light shading (partial utilization - pink or cyan). Molecules that appear to exhibit differential or controversial function (mixed bluered) in certain diseases, or for which there are no data (grey shading) are also noted.
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Author Manuscript Author Manuscript Figure 2. Co-stimulatory and co-inhibitory pathways in Rheumatoid Arthritis (RA)
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The hierarchical utilization of co-stimulatory and co-inhibitory receptors and their corresponding ligands is compared in RA. The extent to which a co-stimulatory or coinhibitory molecule is utilized is indicted by dark (dominant utilization - red or blue) or light shading (partial utilization - pink or cyan). Molecules that appear to exhibit differential or controversial function (mixed bluered) in certain diseases, or for which there are no data (grey shading) are also noted.
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Figure 3. Co-stimulatory and co-inhibitory pathways in Multiple Sclerosis (MS)
The hierarchical utilization of co-stimulatory and co-inhibitory receptors and their corresponding ligands is compared in MS. The extent to which a co-stimulatory or coinhibitory molecule is utilized is indicted by dark (dominant utilization - red or blue) or light shading (partial utilization - pink or cyan). Molecules that appear to exhibit differential or controversial function (mixed bluered) in certain diseases, or for which there are no data (grey shading) are also noted.
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Figure 4. Co-stimulatory and co-inhibitory pathways in Type 1 Diabetes (T1D)
The hierarchical utilization of co-stimulatory and co-inhibitory receptors and their corresponding ligands is compared in T1D. The extent to which a co-stimulatory or coinhibitory molecule is utilized is indicted by dark (dominant utilization - red or blue) or light shading (partial utilization - pink or cyan). Molecules that appear to exhibit differential or controversial function (mixed bluered) in certain diseases, or for which there are no data (grey shading) are also noted.
Author Manuscript Immunity. Author manuscript; available in PMC 2017 May 17.
