Abstract
αβT cell receptor (TCR) genetic diversity is outnumbered by the quantity of pathogenic epitopes to be recognized. To provide efficient protective anti-viral immunity, a single TCR ideally needs to cross-react with a multitude of pathogenic epitopes. However, the frequency, extent, and mechanisms of TCR cross-reactivity remain unclear, with conflicting results on anti-viral T cell cross-reactivity observed in humans. Namely, both the presence and lack of T cell cross-reactivity have been reported with HLA-A*02:01-restricted epitopes from the Epstein-Barr and influenza viruses (BMLF-1 and M158, respectively) or with the hepatitis C and influenza viruses (NS31073 and NA231, respectively). Given the high sequence similarity of these paired viral epitopes (56 and 88%, respectively), the ubiquitous nature of the three viruses, and the high frequency of the HLA-A*02:01 allele, we selected these epitopes to establish the extent of T cell cross-reactivity. We combined ex vivo and in vitro functional assays, single-cell αβTCR repertoire sequencing, and structural analysis of these four epitopes in complex with HLA-A*02:01 to determine whether they could lead to heterologous T cell cross-reactivity. Our data show that sequence similarity does not translate to structural mimicry of the paired epitopes in complexes with HLA-A*02:01, resulting in induction of distinct αβTCR repertoires. The differences in epitope architecture might be an obstacle for TCR recognition, explaining the lack of T cell cross-reactivity observed. In conclusion, sequence similarity does not necessarily result in structural mimicry, and despite the need for cross-reactivity, antigen-specific TCR repertoires can remain highly specific.
Highlights
␣T cell receptor (TCR) genetic diversity is outnumbered by the quantity of pathogenic epitopes to be recognized
T cell cross-reactivity is critical for the efficacy of the immune system, 4 The abbreviations used are: HLA, human leukocyte antigen; TCR, T cell receptor; PDB, Protein Data Bank; EBV, Epstein-Barr virus; HCV, hepatitis C virus; NHMRC, National Health and Medical Research Council; complementarity determining regions (CDRs), complementarity determining region; LCMV, lymphocytic choriomeningitis virus; VV, vaccinia virus; Pn, position n; aa, amino acid(s); peripheral blood mononuclear cells (PBMCs), peripheral blood mononuclear cell; ICS, intracellular cytokine staining; PFA, paraformaldehyde; APC, antigen presenting cell; PE, Phycoerythrin
The thermal melting point (Tm) values were very similar for the paired pHLA complexes, with a Tm of ϳ59 °C for M158 and BMLF-1 and of ϳ56 °C for NA231 and NS31073, suggesting that each pHLA complex displays similar stability
Summary
␣T cell receptor (TCR) genetic diversity is outnumbered by the quantity of pathogenic epitopes to be recognized. The frequency, extent, and mechanisms of TCR crossreactivity remain unclear, with conflicting results on anti-viral T cell cross-reactivity observed in humans. Because the weight of 1015 T cells would be more than 500 kg in one individual, such single specificity of T cells is mathematically impossible This suggests that each T cell must be able to recognize a vast number of peptides to ensure protective immunity in a process known as cross-reactivity. Despite sharing only three identical residues, the two pMHC complexes adopted similar structures, with the variable amino acids buried within the antigen-binding cleft, providing a molecular basis for T cell cross-reactivity (14)
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