Editors' ChoiceAutoimmunity

The good and bad of T cell promiscuity

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Science Translational Medicine  01 Jun 2016:
Vol. 8, Issue 341, pp. 341ec88
DOI: 10.1126/scitranslmed.aag1704

Somatic gene rearrangement of the αβ T cell receptor (TCR) generates a diverse pool of naïve T cells, which should theoretically recognize all foreign peptides (> than 1015) that might be encountered in a lifetime. Current studies estimate less than 108 distinct TCRs in the human naïve T cell pool, which, to avoid immune blind spots, are likely promiscuous in their peptide binding at the risk of increased self-recognition. Cole et al. provide structural evidence for the mechanism of promiscuous binding of a human diabetogenic CD8+ T cell clone and cross-reactivity with pathogen-derived peptides, suggesting molecular mimicry as mechanism of autoimmunity.

The authors previously demonstrated that the human 1E6 CD8+ T cell clone, which mediates the destruction of β cells leading to diabetes, could recognize up to one million different peptide sequences. In this work, they demonstrate that the 1E6 TCR functionally binds multiple ligands over a wide range of affinities. Notably, peptides were identified with higher, antipathogen-like affinity for 1E6 than the endogenous self-peptide. High-resolution, structural analysis of the 1E6 TCR bound to multiple altered peptide ligands identified a conserved minimal binding motif that allowed for TCR binding to ligands with various flanking sequences. Ligands requiring minimal conformational change during binding achieved antipathogen-like affinity. These data indicate that foreign peptides with high affinity to endogenous TCRs may activate T cells capable of cross-reactivity with typically weak self-peptides, leading to a breakdown of tolerance and autoimmunity. In support of this, hundreds of unique peptide sequences from viruses shared the identified hotspot motif, with a subset containing additional hydrophobic amino acid residues that would allow binding to the MHC molecule recognized by 1E6. These data support the hypothesis of molecular mimicry where epitope similarity between microbial and self-proteins generates T cell cross-reactivity and are consistent with evidence that infection can precipitate autoimmunity.

D. K. Cole et al., Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity. J. Clin. Invest. 10.1172/JCI85679 (2016). [Full Text]

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