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T-cells behaving badly: structural insights into alloreactivity and autoimmunity
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T-cells behaving badly: structural insights into alloreactivity and autoimmunity Lauren K Ely1, Scott R Burrows2, Anthony W Purcell3, Jamie Rossjohn4 and James McCluskey5 T-cells play a critical role in protective immunity, with their broad receptor repertoire capable of engaging diverse foreign pMHC landscapes. While the versatility and specificity of this MHC-restricted response is the hallmark of adaptive immunity, unwanted TCR interactions can profoundly effect the health of the host leading for instance to allograft rejection or autoimmunity. In allogeneic transplantation, such adverse reactions can occur by an indirect pathway when the TCR interacts with self-MHC molecules presenting allogeneic MHC derived peptides. Direct T-cell alloreactivity involves recognition of the allogeneic molecule itself either through molecular mimicry or by novel pMHC binding modes. By contrast, auto-reactive TCRs are considered to interact in a manner distinct from cognate pMHC interactions. Here we review recent advances in the field, focusing on structural data pertaining to alloreactivity and auto-reactivity and discuss implications for T-cell mediated transplant rejection and autoimmune disorders. Addresses 1 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA 2 Cellular Immunology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia 3 Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia 4 Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia 5 Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia Corresponding author: Rossjohn, Jamie ([email protected]) and McCluskey, James ([email protected])
Current Opinion in Immunology 2008, 20:575–580 This review comes from a themed issue on Immunogenetics and Transplantation Edited by Frans H. J. Claas and Rene Duquesnoy Available online 12th August 2008 0952-7915/$ – see front matter # 2008 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2008.07.006
Introduction Major histocompatibility complex (MHC) molecules exhibit remarkable polymorphism, with the majority of polymorphisms concentrated in the antigen (Ag)-binding cleft www.sciencedirect.com
creating a diverse array of potential T-cell receptor (TCR) binding sites [1]. The Ag-binding cleft comprises two long a-helices that encapsulate the antigenic peptide, thereby forming a composite TCR binding site. The polymorphism within the Ag-binding cleft can either directly or indirectly impact on TCR recognition, the latter occurring via alteration of the peptide repertoire, peptide conformation or the juxtapositioning of the a-helices [2]. During development, an individual’s T-cell population undergoes thymic selection, resulting in a mature T-cell repertoire that is restricted to recognize self-MHC molecules (Figure 1a), is tolerant of self-peptide–MHC (pMHC) complexes and adept to mounting an immune response to foreign peptides in the context of self-MHC molecules (Figure 1b). However, there are two major exceptions to this paradigm: Tcell allorecognition and T-cell autoimmunity (Figure 1c– f). Allorecognition occurs when the immune system is presented with pMHC ligands of varying allotype to that of the host. T-cell mediated alloreactivity becomes clinically significant in the case of solid-organ grafts or bone marrow transplants in which mismatched MHC molecules can potentially result in organ graft rejection or graftversus-host disease (GVHD). This response can be either direct, in which the T-cells mount an immune response to the foreign-pMHC (Figure 1d) or indirect, a chronic selfMHC restricted response resulting from polymorphism in the processed antigen that can include peptides from allogeneic MHC molecules (Figure 1e). In MHC-matched donor–recipient-pairs minor histocompatibility antigens (mHAgs), derived from intracellular polymorphic proteins, can also cause graft-rejection or GVHD (Figure 1f) (for review see [3]). Given that, during thymic selection the T-cell repertoire is positively selected to recognize self-MHC molecules, direct allorecognition is somewhat of a conundrum; for instance, we do not understand why there are dominance hierarchies in T cell responses to allogeneic MHC-I proteins with greater responses towards HLA-B molecules than HLA-A [4]. Even more perplexing is the high frequency of alloreactive TCRs that is many orders of magnitude greater than that of the cognate response [5]. Nevertheless, allorecognition is observed at a similar frequency to the cross-reactivity of the pre-thymically selected T-cell repertoire suggesting that these cross-interactions may be partly inherent [6] as well as being influenced by selection [2,7]. Structural studies have begun to address the cross-reactive nature of TCRs looking for interaction motifs between the germlineencoded regions of the TCR and the MHC molecule helices. Current Opinion in Immunology 2008, 20:575–580
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Figure 1
The spectrum of TCR–pMHC interactions. The peptide and MHC form a composite binding interface for the TCR; in different scenarios the contribution of the peptide and MHC to TCR recognition may vary, described here by major (big star) and minor (little star) binding-determinants. (a) In positive selection the TCR (turquoise) must bind self-MHC (orange) presenting self-peptides (orange). (b) TCRs bind to foreign peptides (yellow) presented by self-MHC molecules to initiate an immune response. (c) Auto-reactive TCRs trigger an immune reaction in response to self-peptides presented by selfMHC molecules. (d) Alloreactive TCRs bind and signal in response to foreign-pMHC molecules (pink), (e) self-MHC molecules presenting foreign peptides via indirect allorecognition and (f) minor Ags (purple) presented by self-MHC molecules. TCR, T-cell receptor; MHC, major histocompatibility complex; Ag, antigen.
As well as their inherent cross-reactivity, T cells sometimes inadvertently react aggressively on self-pMHC complexes reflecting leakiness in self-tolerance mechanisms and raising the question of whether these autoimmune ‘escapee’ T cells have an unusual mode of TCR binding to self-pMHC complexes. Here we examine our current understanding of the structural basis for T cell recognition during alloreactivity and autoimmunity and their relationship to the emerging principles of cognate TCR-pMHC interactions.
TCR recognition of pMHC The structures of more than 20 unique TCR–pMHC complexes have been solved to date (for review see [8,9]). From this growing structural database it is apparent that a rough docking mode between the TCR–pMHC is preserved, in which the Va domain is positioned over the a2-helix and the N-terminal end of the peptide and the Vb domain is positioned over the a1-helix and Cterminal end of the peptide (Figure 2a). Within this Current Opinion in Immunology 2008, 20:575–580
docking framework, the role of the complementary-determining region (CDR) loops can vary between the TCR– pMHC complexes, such that it is inaccurate to state categorically that the CDR1 and 2 loops contact the MHC while the CDR3 loops contact the peptide. Consistent with this, biophysical analyses of the TCR–pMHC interaction have highlighted the variability of the contributions of the CDR loops to the energetics of the interaction (for example [10]). Structural studies of TCRs in both the non-liganded and liganded conformations can show a large degree of plasticity in the CDR regions, indicating an adaptable nature to accommodate divergent ligands. Moreover, it is also now appreciated that the peptide bound within the Ag-binding cleft can sometimes show marked flexibility upon TCR ligation [11]. Despite the large number of structural studies focused on TCR–pMHC binding, no conserved TCR–MHC interactions are readily apparent. A number of studies have approached the question of defining the underlying www.sciencedirect.com
T-cell allorecognition and auto-reactivity Ely et al. 577
Figure 2
Comparison of TCR interactions with cognate, alloreactive and autoimmune pMHC complexes. The TCR binding-interface on the MHC molecules is shown in the space-filled representation (class I, green; class II, light blue), the peptide is depicted as sticks with the cognate peptides in orange and the allo/autoimmune peptides in yellow. The binding footprints of the TCRs are depicted by the complementarity-determining region (CDR) loops; achain CDR loops, magenta; b-chain, purple. (a) Cognate 2C TCR–dev8-H-2Kb, (b) alloreactive 2C TCR-QL9-H-2Ld, (c) cognate HA1.7 TCR-HA-HLADR, (d) autoimmune Ob1A12 TCR-MBP-HLA-DR. PDB codes 2CKB, 2OI9, 1FYT and 1YMM, respectively.
structural basis for MHC-restriction by using highly focused responses or TCR–pMHC systems that may be considered atypical. For example, two recent reports have looked at murine TCRs that utilize a conserved Vbchain (Vb8.2) binding to a single MHC-allotype [12,13]. Despite variation in the Va-chain and CDR3 regions the authors observed a number of conserved ‘interaction codons’ between the Vb8.2 and the MHC, although these interaction codons do not extend across to Vb8.2 interactions with the MHC-like molecule CD1d [14–16]. Dai and colleagues selected three TCRs of varying specificity. The more cross-reactive TCRs had a reduced number of residues that contacted the MHC; interestingly, the limited MHC-interactions made by the cross-reactive TCRs were conserved in the highly pMHC-specific TCR– MHC interface. Tynan et al. employed a different approach whereby they determined the structure of a TCR bound to an unusually long 13-mer peptide presented by HLA-B*3508 [17]. As the lengthy peptide bulged out of the Ag-binding cleft, the TCR formed a minimal binding footprint on the MHC. The authors propose that these limited contacts represent those essenwww.sciencedirect.com
tial for TCR-recognition of MHC molecules, summarizing three residues as a ‘restriction triad’, which are indeed contacted in all TCR–pMHC structures determined to date. These observations, echoed in a recent review [8], may be the first structural evidence supporting the co-evolution of the MHC and TCR variable genes, a theory postulated by Jerne almost forty years ago [18]; nevertheless more studies will be required to fully appreciate the extent of these cognate interactions and their potential role in allorecognition and auto-reactivity.
Structural insights into TCR allorecognition Structural studies of alloreactive TCRs have been largely hindered due to the limited number of systems for which the cognate and allogeneic pMHC has been defined [19]. Several studies have resolved the interactions of known alloreactive TCRs with their cognate pMHC [17,20,21] or allogeneic pMHC [22,23]; the latter structures demonstrated that alloreactive TCRs bind pMHC with a similar register to that of cognate interactions and could potentially interact with common residues on the self and Current Opinion in Immunology 2008, 20:575–580
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allogeneic MHC molecules pointing towards the peptide as the major allogeneic determinant (for review see [24,25]). A significant breakthrough in our understanding of the molecular basis of allorecognition came in 2007 with the crystal structure of the alloreactive 2C TCR in complex with a foreign pMHC molecule [26]. This study was important as it is the first where both a self(H-2Kb) and allogeneic pMHC (H-2Ld) complex structures were available thus allowing a direct comparison of how a single TCR is able to recognize two diverse ligands (Figure 2a,b). While there was postulation that allorecognition would be governed by molecular mimicry, this is not apparent in this system. Only four of the polymorphic residues that differentiate H-2Ld and H-2Kb are exposed on the a-helices of the MHC and thus available for direct interaction with the TCR. Nevertheless, despite the similar molecular surfaces, the 2C TCR formed predominately unique interactions with the two MHC molecules suggesting that the binding is peptide-centric. However, further structural studies by Colf et al. indicated that in the 2C system the peptide-interactions are not governing the binding orientation but rather the 2C TCR has two unique binding solutions for the syngeneic and allogeneic MHC molecules. Allen and colleagues also recently addressed the role of the allopeptide, whereby they studied a cohort of alloreactive TCRs that included alloreactive TCRs that are specific for a single pMHC and others that recognize two or three different peptides bound to the same MHC molecule [27]. The binding of both these TCRs were sensitive to single alanine substitutions in the peptide, suggesting that despite the polyspecificity of one TCR subset, these TCRs still maintain highly peptide-specific interactions. When considering the overall binding footprint they found that the alloreactive TCRs recognize distinct MHC residues in the presence of different peptides however have a similar global footprint. Together these studies suggest that the role of the allopeptide may vary according to the context of different allorecognition systems and furthermore, the binding strategies employed by alloreactive TCRs are more diverse than previously anticipated.
TCR auto-reactivity One interesting question that arises is, should we anticipate allorecognition to be any different from cognate TCR–pMHC interactions? Furthermore, will these interactions differ again from autoimmune TCR recognition of self-pMHC? If TCRs are inherently biased to recognize MHC then one would anticipate that all interactions would have a similar topography, leaving thymic selection to fine-tune an individual’s T-cell repertoire removing those cells that elicit ‘inappropriate’ responses. T-cell autoimmunity is thought to be the result of auto-reactive T-cells that have escaped negative selection in the thymus [28]. These T-cells are activated by tissue-specific Current Opinion in Immunology 2008, 20:575–580
self-peptides presented by self-MHC molecules resulting in an immune response that causes host tissue destruction. The structures of autoimmune TCR–pMHC complexes from three different systems have been solved to date [13,29–31]. These structures have all examined TCR recognition of self-antigens involved in multiple sclerosis (or the experimental autoimmune encephalomyelitis (EAE) model in mice): two with human TCRs, Ob.1A12 and 3A6, that recognize myelin basic protein (MBP) peptides presented by HLA-DR allotypes, and the third with a series of murine TCRs bound to an MBP peptide-I-Au complex. The two human TCR–pMHC complexes revealed the autoimmune TCRs adopt an unusual binding footprint whereby the TCR docked over the N-terminus of the peptide (Figure 2c,d), although this was not observed in the I-Au complexes. What is distinct about the TCR–MBP-I-Au complexes is the limited number of peptide side-chain-specific interactions with the majority of the peptide–TCR interactions being mediated by main-chain atoms. Although these structures appear to represent oddities in TCR–pMHC recognition, a more extensive structural database will be required to fully derive if autoimmune TCR recognition is truly divergent from that of cognate and allogeneic interactions. While there may be no set rules for autoimmune TCR recognition of pMHC, there appears to be a general trend for auto-reactive TCRs to form suboptimal interactions through a variety of different strategies that ultimately allow these TCRs to escape negative selection.
Do bigger differences equal bigger responses? Much of the focus in matching suitable donor–recipientpairs for allogeneic transplants rests with finding potential donors with minimal genetic variation between their respective MHC molecules. In the case when genetically identical donors are not available the optimal donor selection may not be so clear. With regards to B-cell mediated allograft rejection it has become evident that the potential immunogenicity can be reasonably predicted by comparing defined patches of polymorphic residues, which are potential antibody epitopes, on the HLA molecular surface using an algorithm implemented by the program HLAMatchmaker [32,33]. For T-cell mediated alloreactivity the potential impact of polymorphic residues is more complex. While many of the described alloresponses occur across HLA-allotypes, mismatches between HLA-subtypes diverging only at a single amino acid have also been reported to cause graft rejection [34–36]. If molecular mimicry is a common perpetrator for instigating alloresponses than it follows that increasing the diversity between unmatched allotypes would reduce the chances of T-cell mediated crossreactivity. Heemskerk and colleagues showed for single mismatches at HLA-C, increasing the number of polymorphic residues between the HLA allotypes decreased the alloreactivity in vitro and increased patient survival www.sciencedirect.com
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rates [37,38]. Interestingly, the frequency of alloresponses across MHC classes and indeed species barriers is lower than those within a given system [5]. This may reflect, in part, the role of the class-dependent co-receptors, CD4 and CD8, to fine-tune the specificity of the alloresponse [39]; an effect that would be magnified in the case of xeno-reactivity as the co-receptors are known to have a level of species specificity [40].
Why do alloresponses occur at such a high frequency? The frequency of alloreactive CTLs is estimated to be up to 10%, approximately 1000-fold the frequency at which T cells recognize self-MHC with foreign peptide [5,41]. The underlying reason for the elevated level of alloreactive T cells has long been debated. Two polar theories were originally proposed: the first, that the alloreactive T cells recognize a multitude of new pMHC complexes predominantly focused on the peptide and thus ‘determinant frequency’ drives allorecognition [42]. The second, that the high ‘determinant density’ of foreign MHC molecules stimulates the response due to the MHC polymorphic residues with no influence from the peptide [43]. Current data suggests that allo-interactions are likely to manifest from the recognition of the composite surface formed by both the peptide and MHC molecule. Alloreactive TCRs with multiple peptide specificities isolated by the Allen group give some insight into how such a high frequency of allorecognition can be achieved [27]. Nevertheless, it seems somewhat implausible that multiple peptide specificity can account for the extent of cross-reactivity. A second contributing factor may be the presence of dominant T-cell populations and/or peptide epitopes. At both the level of thymic selection and in response to viral antigen the T-cell repertoire can become significantly biased (for review see [44]), if grossly over represented T-cells are able to mediate an alloresponse then the apparent frequency of alloreactive clones would be significantly higher than that anticipated for a truly diverse repertoire. On the flipside, MHC molecules can present dominant peptides from viral proteins at very high abundance; such biased presentation of endogenous peptide could also drive a significantly elevated alloresponse. Finally, it remains unclear to what extent there is a germline bias for TCR to recognize MHC. If the TCR has a low affinity for all MHC molecules then perhaps the alloresponse is determined by the array of peptides presented.
Conclusions During the past few years, significant progress has been made towards understanding the structural basis of allogeneic and autoimmune TCR recognition. Nevertheless, these systems are extremely complex and any ‘rules’ cannot be deduced emphatically from such a limited number of structures. Hence, to fully appreciate the driving forces behind the high frequency of cross-reactive www.sciencedirect.com
TCRs, including the implications this has for allograft rejection and autoimmunity, we need to first further understand the structural basis and thus potential diversity of this recognition.
Acknowledgements This work was supported by grants from the National Health and Medical Research Council (NHMRC), Australian Research Council (ARC) and Roche Organ Transplant Research Foundation. LKE is an NHMRC CJ Martin Fellow, SRB and AWP NHMRC Senior Research Fellows and JR an ARC Federation Fellow.
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T-cells behaving badly: structural insights into alloreactivity and autoimmunity Lauren K Ely1, Scott R Burrows2, Anthony W Purcell3, Jamie Rossjohn4 and James McCluskey5 T-cells play a critical role in protective immunity, with their broad receptor repertoire capable of engaging diverse foreign pMHC landscapes. While the versatility and specificity of this MHC-restricted response is the hallmark of adaptive immunity, unwanted TCR interactions can profoundly effect the health of the host leading for instance to allograft rejection or autoimmunity. In allogeneic transplantation, such adverse reactions can occur by an indirect pathway when the TCR interacts with self-MHC molecules presenting allogeneic MHC derived peptides. Direct T-cell alloreactivity involves recognition of the allogeneic molecule itself either through molecular mimicry or by novel pMHC binding modes. By contrast, auto-reactive TCRs are considered to interact in a manner distinct from cognate pMHC interactions. Here we review recent advances in the field, focusing on structural data pertaining to alloreactivity and auto-reactivity and discuss implications for T-cell mediated transplant rejection and autoimmune disorders. Addresses 1 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA 2 Cellular Immunology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia 3 Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia 4 Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia 5 Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia Corresponding author: Rossjohn, Jamie ([email protected]) and McCluskey, James ([email protected])
Current Opinion in Immunology 2008, 20:575–580 This review comes from a themed issue on Immunogenetics and Transplantation Edited by Frans H. J. Claas and Rene Duquesnoy Available online 12th August 2008 0952-7915/$ – see front matter # 2008 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2008.07.006
Introduction Major histocompatibility complex (MHC) molecules exhibit remarkable polymorphism, with the majority of polymorphisms concentrated in the antigen (Ag)-binding cleft www.sciencedirect.com
creating a diverse array of potential T-cell receptor (TCR) binding sites [1]. The Ag-binding cleft comprises two long a-helices that encapsulate the antigenic peptide, thereby forming a composite TCR binding site. The polymorphism within the Ag-binding cleft can either directly or indirectly impact on TCR recognition, the latter occurring via alteration of the peptide repertoire, peptide conformation or the juxtapositioning of the a-helices [2]. During development, an individual’s T-cell population undergoes thymic selection, resulting in a mature T-cell repertoire that is restricted to recognize self-MHC molecules (Figure 1a), is tolerant of self-peptide–MHC (pMHC) complexes and adept to mounting an immune response to foreign peptides in the context of self-MHC molecules (Figure 1b). However, there are two major exceptions to this paradigm: Tcell allorecognition and T-cell autoimmunity (Figure 1c– f). Allorecognition occurs when the immune system is presented with pMHC ligands of varying allotype to that of the host. T-cell mediated alloreactivity becomes clinically significant in the case of solid-organ grafts or bone marrow transplants in which mismatched MHC molecules can potentially result in organ graft rejection or graftversus-host disease (GVHD). This response can be either direct, in which the T-cells mount an immune response to the foreign-pMHC (Figure 1d) or indirect, a chronic selfMHC restricted response resulting from polymorphism in the processed antigen that can include peptides from allogeneic MHC molecules (Figure 1e). In MHC-matched donor–recipient-pairs minor histocompatibility antigens (mHAgs), derived from intracellular polymorphic proteins, can also cause graft-rejection or GVHD (Figure 1f) (for review see [3]). Given that, during thymic selection the T-cell repertoire is positively selected to recognize self-MHC molecules, direct allorecognition is somewhat of a conundrum; for instance, we do not understand why there are dominance hierarchies in T cell responses to allogeneic MHC-I proteins with greater responses towards HLA-B molecules than HLA-A [4]. Even more perplexing is the high frequency of alloreactive TCRs that is many orders of magnitude greater than that of the cognate response [5]. Nevertheless, allorecognition is observed at a similar frequency to the cross-reactivity of the pre-thymically selected T-cell repertoire suggesting that these cross-interactions may be partly inherent [6] as well as being influenced by selection [2,7]. Structural studies have begun to address the cross-reactive nature of TCRs looking for interaction motifs between the germlineencoded regions of the TCR and the MHC molecule helices. Current Opinion in Immunology 2008, 20:575–580
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Figure 1
The spectrum of TCR–pMHC interactions. The peptide and MHC form a composite binding interface for the TCR; in different scenarios the contribution of the peptide and MHC to TCR recognition may vary, described here by major (big star) and minor (little star) binding-determinants. (a) In positive selection the TCR (turquoise) must bind self-MHC (orange) presenting self-peptides (orange). (b) TCRs bind to foreign peptides (yellow) presented by self-MHC molecules to initiate an immune response. (c) Auto-reactive TCRs trigger an immune reaction in response to self-peptides presented by selfMHC molecules. (d) Alloreactive TCRs bind and signal in response to foreign-pMHC molecules (pink), (e) self-MHC molecules presenting foreign peptides via indirect allorecognition and (f) minor Ags (purple) presented by self-MHC molecules. TCR, T-cell receptor; MHC, major histocompatibility complex; Ag, antigen.
As well as their inherent cross-reactivity, T cells sometimes inadvertently react aggressively on self-pMHC complexes reflecting leakiness in self-tolerance mechanisms and raising the question of whether these autoimmune ‘escapee’ T cells have an unusual mode of TCR binding to self-pMHC complexes. Here we examine our current understanding of the structural basis for T cell recognition during alloreactivity and autoimmunity and their relationship to the emerging principles of cognate TCR-pMHC interactions.
TCR recognition of pMHC The structures of more than 20 unique TCR–pMHC complexes have been solved to date (for review see [8,9]). From this growing structural database it is apparent that a rough docking mode between the TCR–pMHC is preserved, in which the Va domain is positioned over the a2-helix and the N-terminal end of the peptide and the Vb domain is positioned over the a1-helix and Cterminal end of the peptide (Figure 2a). Within this Current Opinion in Immunology 2008, 20:575–580
docking framework, the role of the complementary-determining region (CDR) loops can vary between the TCR– pMHC complexes, such that it is inaccurate to state categorically that the CDR1 and 2 loops contact the MHC while the CDR3 loops contact the peptide. Consistent with this, biophysical analyses of the TCR–pMHC interaction have highlighted the variability of the contributions of the CDR loops to the energetics of the interaction (for example [10]). Structural studies of TCRs in both the non-liganded and liganded conformations can show a large degree of plasticity in the CDR regions, indicating an adaptable nature to accommodate divergent ligands. Moreover, it is also now appreciated that the peptide bound within the Ag-binding cleft can sometimes show marked flexibility upon TCR ligation [11]. Despite the large number of structural studies focused on TCR–pMHC binding, no conserved TCR–MHC interactions are readily apparent. A number of studies have approached the question of defining the underlying www.sciencedirect.com
T-cell allorecognition and auto-reactivity Ely et al. 577
Figure 2
Comparison of TCR interactions with cognate, alloreactive and autoimmune pMHC complexes. The TCR binding-interface on the MHC molecules is shown in the space-filled representation (class I, green; class II, light blue), the peptide is depicted as sticks with the cognate peptides in orange and the allo/autoimmune peptides in yellow. The binding footprints of the TCRs are depicted by the complementarity-determining region (CDR) loops; achain CDR loops, magenta; b-chain, purple. (a) Cognate 2C TCR–dev8-H-2Kb, (b) alloreactive 2C TCR-QL9-H-2Ld, (c) cognate HA1.7 TCR-HA-HLADR, (d) autoimmune Ob1A12 TCR-MBP-HLA-DR. PDB codes 2CKB, 2OI9, 1FYT and 1YMM, respectively.
structural basis for MHC-restriction by using highly focused responses or TCR–pMHC systems that may be considered atypical. For example, two recent reports have looked at murine TCRs that utilize a conserved Vbchain (Vb8.2) binding to a single MHC-allotype [12,13]. Despite variation in the Va-chain and CDR3 regions the authors observed a number of conserved ‘interaction codons’ between the Vb8.2 and the MHC, although these interaction codons do not extend across to Vb8.2 interactions with the MHC-like molecule CD1d [14–16]. Dai and colleagues selected three TCRs of varying specificity. The more cross-reactive TCRs had a reduced number of residues that contacted the MHC; interestingly, the limited MHC-interactions made by the cross-reactive TCRs were conserved in the highly pMHC-specific TCR– MHC interface. Tynan et al. employed a different approach whereby they determined the structure of a TCR bound to an unusually long 13-mer peptide presented by HLA-B*3508 [17]. As the lengthy peptide bulged out of the Ag-binding cleft, the TCR formed a minimal binding footprint on the MHC. The authors propose that these limited contacts represent those essenwww.sciencedirect.com
tial for TCR-recognition of MHC molecules, summarizing three residues as a ‘restriction triad’, which are indeed contacted in all TCR–pMHC structures determined to date. These observations, echoed in a recent review [8], may be the first structural evidence supporting the co-evolution of the MHC and TCR variable genes, a theory postulated by Jerne almost forty years ago [18]; nevertheless more studies will be required to fully appreciate the extent of these cognate interactions and their potential role in allorecognition and auto-reactivity.
Structural insights into TCR allorecognition Structural studies of alloreactive TCRs have been largely hindered due to the limited number of systems for which the cognate and allogeneic pMHC has been defined [19]. Several studies have resolved the interactions of known alloreactive TCRs with their cognate pMHC [17,20,21] or allogeneic pMHC [22,23]; the latter structures demonstrated that alloreactive TCRs bind pMHC with a similar register to that of cognate interactions and could potentially interact with common residues on the self and Current Opinion in Immunology 2008, 20:575–580
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allogeneic MHC molecules pointing towards the peptide as the major allogeneic determinant (for review see [24,25]). A significant breakthrough in our understanding of the molecular basis of allorecognition came in 2007 with the crystal structure of the alloreactive 2C TCR in complex with a foreign pMHC molecule [26]. This study was important as it is the first where both a self(H-2Kb) and allogeneic pMHC (H-2Ld) complex structures were available thus allowing a direct comparison of how a single TCR is able to recognize two diverse ligands (Figure 2a,b). While there was postulation that allorecognition would be governed by molecular mimicry, this is not apparent in this system. Only four of the polymorphic residues that differentiate H-2Ld and H-2Kb are exposed on the a-helices of the MHC and thus available for direct interaction with the TCR. Nevertheless, despite the similar molecular surfaces, the 2C TCR formed predominately unique interactions with the two MHC molecules suggesting that the binding is peptide-centric. However, further structural studies by Colf et al. indicated that in the 2C system the peptide-interactions are not governing the binding orientation but rather the 2C TCR has two unique binding solutions for the syngeneic and allogeneic MHC molecules. Allen and colleagues also recently addressed the role of the allopeptide, whereby they studied a cohort of alloreactive TCRs that included alloreactive TCRs that are specific for a single pMHC and others that recognize two or three different peptides bound to the same MHC molecule [27]. The binding of both these TCRs were sensitive to single alanine substitutions in the peptide, suggesting that despite the polyspecificity of one TCR subset, these TCRs still maintain highly peptide-specific interactions. When considering the overall binding footprint they found that the alloreactive TCRs recognize distinct MHC residues in the presence of different peptides however have a similar global footprint. Together these studies suggest that the role of the allopeptide may vary according to the context of different allorecognition systems and furthermore, the binding strategies employed by alloreactive TCRs are more diverse than previously anticipated.
TCR auto-reactivity One interesting question that arises is, should we anticipate allorecognition to be any different from cognate TCR–pMHC interactions? Furthermore, will these interactions differ again from autoimmune TCR recognition of self-pMHC? If TCRs are inherently biased to recognize MHC then one would anticipate that all interactions would have a similar topography, leaving thymic selection to fine-tune an individual’s T-cell repertoire removing those cells that elicit ‘inappropriate’ responses. T-cell autoimmunity is thought to be the result of auto-reactive T-cells that have escaped negative selection in the thymus [28]. These T-cells are activated by tissue-specific Current Opinion in Immunology 2008, 20:575–580
self-peptides presented by self-MHC molecules resulting in an immune response that causes host tissue destruction. The structures of autoimmune TCR–pMHC complexes from three different systems have been solved to date [13,29–31]. These structures have all examined TCR recognition of self-antigens involved in multiple sclerosis (or the experimental autoimmune encephalomyelitis (EAE) model in mice): two with human TCRs, Ob.1A12 and 3A6, that recognize myelin basic protein (MBP) peptides presented by HLA-DR allotypes, and the third with a series of murine TCRs bound to an MBP peptide-I-Au complex. The two human TCR–pMHC complexes revealed the autoimmune TCRs adopt an unusual binding footprint whereby the TCR docked over the N-terminus of the peptide (Figure 2c,d), although this was not observed in the I-Au complexes. What is distinct about the TCR–MBP-I-Au complexes is the limited number of peptide side-chain-specific interactions with the majority of the peptide–TCR interactions being mediated by main-chain atoms. Although these structures appear to represent oddities in TCR–pMHC recognition, a more extensive structural database will be required to fully derive if autoimmune TCR recognition is truly divergent from that of cognate and allogeneic interactions. While there may be no set rules for autoimmune TCR recognition of pMHC, there appears to be a general trend for auto-reactive TCRs to form suboptimal interactions through a variety of different strategies that ultimately allow these TCRs to escape negative selection.
Do bigger differences equal bigger responses? Much of the focus in matching suitable donor–recipientpairs for allogeneic transplants rests with finding potential donors with minimal genetic variation between their respective MHC molecules. In the case when genetically identical donors are not available the optimal donor selection may not be so clear. With regards to B-cell mediated allograft rejection it has become evident that the potential immunogenicity can be reasonably predicted by comparing defined patches of polymorphic residues, which are potential antibody epitopes, on the HLA molecular surface using an algorithm implemented by the program HLAMatchmaker [32,33]. For T-cell mediated alloreactivity the potential impact of polymorphic residues is more complex. While many of the described alloresponses occur across HLA-allotypes, mismatches between HLA-subtypes diverging only at a single amino acid have also been reported to cause graft rejection [34–36]. If molecular mimicry is a common perpetrator for instigating alloresponses than it follows that increasing the diversity between unmatched allotypes would reduce the chances of T-cell mediated crossreactivity. Heemskerk and colleagues showed for single mismatches at HLA-C, increasing the number of polymorphic residues between the HLA allotypes decreased the alloreactivity in vitro and increased patient survival www.sciencedirect.com
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rates [37,38]. Interestingly, the frequency of alloresponses across MHC classes and indeed species barriers is lower than those within a given system [5]. This may reflect, in part, the role of the class-dependent co-receptors, CD4 and CD8, to fine-tune the specificity of the alloresponse [39]; an effect that would be magnified in the case of xeno-reactivity as the co-receptors are known to have a level of species specificity [40].
Why do alloresponses occur at such a high frequency? The frequency of alloreactive CTLs is estimated to be up to 10%, approximately 1000-fold the frequency at which T cells recognize self-MHC with foreign peptide [5,41]. The underlying reason for the elevated level of alloreactive T cells has long been debated. Two polar theories were originally proposed: the first, that the alloreactive T cells recognize a multitude of new pMHC complexes predominantly focused on the peptide and thus ‘determinant frequency’ drives allorecognition [42]. The second, that the high ‘determinant density’ of foreign MHC molecules stimulates the response due to the MHC polymorphic residues with no influence from the peptide [43]. Current data suggests that allo-interactions are likely to manifest from the recognition of the composite surface formed by both the peptide and MHC molecule. Alloreactive TCRs with multiple peptide specificities isolated by the Allen group give some insight into how such a high frequency of allorecognition can be achieved [27]. Nevertheless, it seems somewhat implausible that multiple peptide specificity can account for the extent of cross-reactivity. A second contributing factor may be the presence of dominant T-cell populations and/or peptide epitopes. At both the level of thymic selection and in response to viral antigen the T-cell repertoire can become significantly biased (for review see [44]), if grossly over represented T-cells are able to mediate an alloresponse then the apparent frequency of alloreactive clones would be significantly higher than that anticipated for a truly diverse repertoire. On the flipside, MHC molecules can present dominant peptides from viral proteins at very high abundance; such biased presentation of endogenous peptide could also drive a significantly elevated alloresponse. Finally, it remains unclear to what extent there is a germline bias for TCR to recognize MHC. If the TCR has a low affinity for all MHC molecules then perhaps the alloresponse is determined by the array of peptides presented.
Conclusions During the past few years, significant progress has been made towards understanding the structural basis of allogeneic and autoimmune TCR recognition. Nevertheless, these systems are extremely complex and any ‘rules’ cannot be deduced emphatically from such a limited number of structures. Hence, to fully appreciate the driving forces behind the high frequency of cross-reactive www.sciencedirect.com
TCRs, including the implications this has for allograft rejection and autoimmunity, we need to first further understand the structural basis and thus potential diversity of this recognition.
Acknowledgements This work was supported by grants from the National Health and Medical Research Council (NHMRC), Australian Research Council (ARC) and Roche Organ Transplant Research Foundation. LKE is an NHMRC CJ Martin Fellow, SRB and AWP NHMRC Senior Research Fellows and JR an ARC Federation Fellow.
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