Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity

Abstract

The cross-reactivity of T cells with pathogen- and self-derived peptides has been implicated as a pathway involved in the development of autoimmunity. However, the mechanisms that allow the clonal T cell antigen receptor (TCR) to functionally engage multiple peptide–major histocompatibility complexes (pMHC) are unclear. Here, we studied multiligand discrimination by a human, preproinsulin reactive, MHC class-I–restricted CD8+ T cell clone (1E6) that can recognize over 1 million different peptides. We generated high-resolution structures of the 1E6 TCR bound to 7 altered peptide ligands, including a pathogen-derived peptide that was an order of magnitude more potent than the natural self-peptide. Evaluation of these structures demonstrated that binding was stabilized through a conserved lock-and-key–like minimal binding footprint that enables 1E6 TCR to tolerate vast numbers of substitutions outside of this so-called hotspot. Highly potent antigens of the 1E6 TCR engaged with a strong antipathogen-like binding affinity; this engagement was governed though an energetic switch from an enthalpically to entropically driven interaction compared with the natural autoimmune ligand. Together, these data highlight how T cell cross-reactivity with pathogen-derived antigens might break self-tolerance to induce autoimmune disease.

How an alloreactive T-cell receptor achieves peptide and MHC specificity

“…Third, where the peptides are most different (p1 Lys in NS3 and p1 Glu in MART-1) is the exact region where substitutions have the greatest impact and direct cross-recognition. HCV1406 cross-reactivity with a modified MART-1 peptide therefore underscores the importance of hot spots in TCR specificity: The TCR engages a key region of the peptide that most directly influences specificity, restricting amino acid composition there but leaving other regions open to more diversity (45,46). Our observations illustrate how hotspots can work alongside mimicry in directing TCR specificity/ cross-reactivity and reinforce how peptide features working alongside the distinctive surface chemistry of allo-MHC can drive allospecificity.…”

Islet-reactive CD8 + T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors

“…Thus, while most children harbor a larger autoimmune repertoire not restricted to islet Ags, the activation of the islet-reactive fraction occurs preferentially in T1D children, which may reflect a more aggressive islet autoimmunity leading to earlier disease onset. On the other hand, some Ag-experienced β-cell-reactive CD8 + T cells were invariably detected in healthy donors, supporting the possibility that foreign epitopes may prime autoreactive clonotypes expressing promiscuous TCRs (22–24). Indeed, some ZnT8 186–194 -reactive CD8 + T-cell clonotypes were able to cross-recognize a B. stercoris mimotope.…”

Autoreactive T cells in type 1 diabetes

“…Enteroviruses may also trigger autoimmunity via presentation of self-molecules in an inflammatory context (bystander activation) (124) and/or by molecular mimicry (125)(126)(127). Cross-reactivities with viral proteins were reported for autoantibody (128)(129)(130)(131)(132)(133)(134) and T cell responses (73,132,(135)(136)(137)(138)(139)(140)(141)(142)(143)(144) with GAD65, IA-2, and insulin autoantigens. β Cell inflammation and ER stress promote β cell dysfunction and immunogenicity, and protein misfolding is associated with abnormal autoantigen presentation (145)(146)(147).…”