Cell Receptor Cross-reactivity Research Articles

T cell receptor cross-reactivity between gliadin and bacterial peptides in celiac disease.

The human leukocyte antigen (HLA) locus is strongly associated with T cell-mediated autoimmune disorders. HLA-DQ2.5-mediated celiac disease (CeD) is triggered by the ingestion of gluten, although the relative roles of genetic and environmental risk factors in CeD is unclear. Here we identify microbially derived mimics of gliadin epitopes and a parental bacterial protein that is naturally processed by antigen-presenting cells and activated gliadin reactive HLA-DQ2.5-restricted T cells derived from CeD patients. Crystal structures of T cell receptors in complex with HLA-DQ2.5 bound to two distinct bacterial peptides demonstrate that molecular mimicry underpins cross-reactivity toward the gliadin epitopes. Accordingly, gliadin reactive T cells involved in CeD pathogenesis cross-react with ubiquitous bacterial peptides, thereby suggesting microbial exposure as a potential environmental factor in CeD.

T cell receptor cross-reactivity expanded by dramatic peptide-MHC adaptability.

T cell receptor cross-reactivity allows a fixed T cell repertoire to respond to a much larger universe of potential antigens. Recent work has emphasized the importance of peptide structural and chemical homology, as opposed to sequence similarity, in T cell receptor cross-reactivity. Surprisingly though, T cell receptors can also cross-react between ligands with little physiochemical commonalities. Studying the clinically relevant receptor DMF5, we demonstrate that cross-recognition of such divergent antigens can occur through mechanisms that involve heretofore unanticipated rearrangements in the peptide and presenting MHC protein, including binding-induced peptide register shifts and extensions from MHC peptide binding grooves. Moreover, cross-reactivity can proceed even when such dramatic rearrangements do not translate into structural or chemical molecular mimicry. Beyond demonstrating new principles of T cell receptor cross-reactivity, our results have implications for efforts to predict and control T cell specificity and cross-reactivity, and highlight challenges associated with predicting T cell reactivities.

Implications of T cell receptor cross-reactivity on the CD4+ T cell repertoire (APP3P.111)

Abstract Naïve CD4+ T cell populations with T cell receptors (TCR) specific for different major histocompatibility complex II (MHCII)-bound foreign peptides vary in size for unknown reasons. Negative selection on self peptides could play a role. We found that MHCII-binding nonamer peptides only had to have the same residues at five positions to be recognized by the same TCR. This degree of TCR cross-reactivity between self and foreign peptides reduced the sizes of foreign peptide-specific T cell populations via clonal deletion. Small foreign p:MHCII-specific populations that underwent a greater degree of cross-reactive negative selection were on average lower affinity and produced more variable effector cell responses to immunization. In contrast, large foreign p:MHCII-specific T cell populations with minimal evidence of negative selection were higher affinity and produced larger responses to immunization. Reciprocally, an incompletely deleted naïve T cell population specific for a tissue-restricted self peptide could be triggered by similar microbial peptides to cause autoimmunity. Thus, TCR cross-reactivity between similar self and foreign peptides influences the size of certain foreign peptide-specific T cell populations, and may allow tissue-restricted self peptide-specific populations to cause autoimmunity after infection.

T Cell Receptor Cross-Reactivity between Similar Foreign and Self Peptides Influences Naive Cell Population Size and Autoimmunity

T cell receptor (TCR) cross-reactivity between major histocompatibility complex II (MHCII)-binding self and foreign peptides could influence the naive CD4(+) T cell repertoire and autoimmunity. We found that nonamer peptides that bind to the same MHCII molecule only need to share five amino acids to cross-react on the same TCR. This property was biologically relevant because systemic expression of a self peptide reduced the size of a naive cell population specific for a related foreign peptide by deletion of cells with cross-reactive TCRs. Reciprocally, an incompletely deleted naive T cell population specific for a tissue-restricted self peptide could be triggered by related microbial peptides to cause autoimmunity. Thus, TCR cross-reactivity between similar self and foreign peptides can reduce the size of certain foreign peptide-specific T cell populations and might allow T cell populations specific for tissue-restricted self peptides to cause autoimmunity after infection.

Understanding MHCII-restricted T cell receptor cross-reactivity to foreign peptides (P5011)

Abstract CD4+ T cells bearing unique T cell receptors (TCRs) recognize antigens in the form of peptides bound to major histocompatibility complex class II proteins (p:MHCII). In mice, structural studies of peptides bound to the MHCII molecule I-Ab have revealed that p:I-Ab complexes consist of a core peptide of at least 9 amino acids. Five of the positions within the nonamer core interact with the peptide binding groove of I-Ab and orient the 4 TCR contact amino acids so that they are accessible for TCR recognition. However, the rules that govern this TCR recognition and cross-reactivity for p:MHCII complexes are largely unknown. Using a p:MHCII-tetramer based approach, we tested the limits of MHCII-restricted TCR cross-reactivity by studying two nonamer peptides with 4 identical TCR contact amino acids but different I-Ab anchor residues. To our surprise, we found that 80% of T cell clones could not discriminate between the two peptides. When we expressed one of the peptides as a self peptide in a transgenic mouse model, we found that the T cell response to immunization with the other peptide was decreased by over 50%. These results could explain how TCR cross-reactivity can account for repertoire selection as well as autoimmunity induced by molecular mimicry.

T Cell Receptor Cross-Reactivity Directed by Antigen Dependent Tuning of Peptide-MHC Molecular Flexibility

T Cell Receptor Cross-Reactivity Directed by Antigen Dependent Tuning of Peptide-MHC Molecular Flexibility

The Multiple Mechanisms of T Cell Receptor Cross-reactivity

The ability of a single T cell to recognize the diverse peptides it encounters is based on T cell receptor crossreactivity. In this issue of Immunity, Macdonald et al. (2009) and Borbulevych et al. (2009) provide new insights into the structural principles underlying this fundamental property of T cells.

T Cell Receptor Cross-reactivity Directed by Antigen-Dependent Tuning of Peptide-MHC Molecular Flexibility

T cell-mediated immunity requires T cell receptor (TCR) cross-reactivity, the mechanisms behind which remain incompletely elucidated. The alphabeta TCR A6 recognizes both the Tax (LLFGYPVYV) and Tel1p (MLWGYLQYV) peptides presented by the human class I MHC molecule HLA-A2. Here we found that although the two ligands are ideal structural mimics, they form substantially different interfaces with A6, with conformational differences in the peptide, the TCR, and unexpectedly, the MHC molecule. The differences between the Tax and Tel1p ternary complexes could not be predicted from the free peptide-MHC structures and are inconsistent with a traditional induced-fit mechanism. Instead, the differences were attributable to peptide and MHC molecular motion present in Tel1p-HLA-A2 but absent in Tax-HLA-A2. Differential "tuning" of the dynamic properties of HLA-A2 by the Tax and Tel1p peptides thus facilitates cross-recognition and impacts how structural diversity can be presented to and accommodated by receptors of the immune system.

T Cell Receptor Recognition via Cooperative Conformational Plasticity

Although T cell receptor cross-reactivity is a fundamental property of the immune system and is implicated in numerous autoimmune pathologies, the molecular mechanisms by which T cell receptors can recognize and respond to diverse ligands are incompletely understood. In the current study we examined the response of the human T cell lymphotropic virus-1 (HTLV-1) Tax-specific T cell receptor (TCR) A6 to a panel of structurally distinct haptens coupled to the Tax 11-19 peptide with a lysine substitution at position 5 (Tax5K, LLFG[K-hapten]PVYV). The A6 TCR could cross-reactively recognize one of these haptenated peptides, Tax-5K-4-(3-Indolyl)-butyric acid (IBA), presented by HLA-A*0201. The crystal structures of Tax5K-IBA/HLA-A2 free and in complex with A6 reveal that binding is mediated by a mechanism of cooperative conformational plasticity involving conformational changes on both sides of the protein–protein interface, including the TCR complementarity determining region (CDR) loops, Vα/Vβ domain orientation, and the hapten-modified peptide. Our findings illustrate the complex role that protein dynamics can play in TCR cross-reactivity and highlight that T cell receptor recognition of ligand can be achieved through diverse and complex molecular mechanisms that can occur simultaneously in the interface, not limited to molecular mimicry and CDR loop shifts.

Extensive T cell receptor cross-reactivity on structurally diverse haptenated peptides presented by HLA-A2

Previous studies have shown that individual TCRs are able to effectively recognize multiple peptide/MHC complexes that have varying degrees of structural diversity. These TCR cross-reactivities have usually been demonstrated by using peptides that have different amino acid sequences. To further examine the extent to which TCRs can accommodate structurally diverse ligands, we analyzed human TCR cross-reactivity to eight structurally distinct haptens that are coupled to the HLA-A2-binding Tax peptide with a lysine substitution at position 5 (Tax-5K, LLFG[K-hapten]PVYV). The results demonstrate that 71% percent of the haptenated-peptide-induced CTL lines could cross-react on at least one other hapten. We compared the effects of HLA-A2 mutants with substitutions at known TCR contact sites for recognition by hapten-cross-reactive CTL. Recognition of the A2 mutants was remarkably similar whether they were presenting the immunizing or the cross-reactive peptide, indicating that similar amino acid contacts are made by the TCR during recognition of both complexes. Thus, hapten cross-reactivity is apparently accomplished without major adjustments to the interaction between the TCR and the surface of the HLA-A2 molecule. Collectively, these results suggest that TCRs possess the molecular flexibility to accommodate very structurally diverse ligands while retaining conserved interactions with the surface of the MHC molecule.

Structure of an Autoimmune T Cell Receptor Complexed with Class II Peptide-MHC: Insights into MHC Bias and Antigen Specificity

T cell receptor crossreactivity with different peptide ligands and biased recognition of MHC are coupled features of antigen recognition that are necessary for the T cell's diverse functional repertoire. In the crystal structure between an autoreactive, EAE T cell clone 172.10 and myelin basic protein (1–11) presented by class II MHC I-A u, recognition of the MHC is dominated by the Vβ domain of the TCR, which interacts with the MHC α chain in a manner suggestive of a germline-encoded TCR/MHC “anchor point.” Strikingly, there are few specific contacts between the TCR CDR3 loops and the MBP peptide. We also find that over 1,000,000 different peptides derived from combinatorial libraries can activate 172.10, yet the TCR strongly prefers the native MBP contact residues. We suggest that while TCR scanning of pMHC may be degenerate due to the TCR germline bias for MHC, recognition of structurally distinct agonist peptides is not indicative of TCR promiscuity, but rather highly specific alternative solutions to TCR engagement.

T cell receptor crossreactivity as a general property of T cell recognition

TCR recognition of MHC/peptide complexes directs many aspects of T cell biology, including thymic selection, survival of naı̈ve T cells and differentiation into effector and memory T cells. It was widely thought that TCR recognition is highly specific, with an individual T cell being capable of only recognizing a particular peptide and closely related sequence variants. By considering the structural requirements for peptide binding to MHC molecules and TCR recognition of MHC/peptide complexes, we demonstrated that T cell clones could recognize a number of peptides from different organisms that are remarkably distinct in their primary sequence. These peptides are particularly diverse at those sequence positions buried in pockets of the MHC binding site, while a higher degree of similarity is present at a limited number of peptide residues that create the interface with the TCR. Many examples have now been documented for human and murine T cells, indicating that TCR crossreactivity represents a general feature of TCR recognition.

Guillain-Barre syndrome and Campylobacter jejuni infection

Guillain-Barre syndrome (GBS) is the most common cause of acute neuromuscular paralysis, usually due to acute inflammatory demyelinating polyradiculoneuropathy. The presence of activated T lymphocytes and antibodies against peripheral nerve myelin suggests an autoimmune pathogenesis, although there is wide heterogeneity. Gangliosides are sialylated glycolipids widely distributed in nervous system membranes. GBS is usually preceded by an infection, most frequently Campylobacter jejuni enteritis, but also cytomegalovirus, Mycoplasma pneumoniae or Epstein-Barr virus. Patients with GBS and C. jejuni infection are more likely to have neurophysiological features of axonal neuropathy, antibodies to ganglioside GM1, pure motor GBS, a less elevated CSF protein concentration and a worse outcome than other GBS patients. Although molecular mimicry between peripheral nerve gangliosides and epitopes present on C. jejuni lipopolysaccharide could explain some of these associations, this hypothesis is inadequate to account for many aspects of the pathogenesis of GBS.