TCR affinity and tolerance mechanisms converge to shape T cell diabetogenic potential

Maria Bettini, Lori Blanchfield, Ashley Castellaw, Qianxia Zhang, Maki Nakayama, Matthew P. Smeltzer, Hui Zhang, Kristin A. Hogquist, Brian D. Evavold, Dario A.A. Vignali*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Autoreactive T cells infiltrating the target organ can possess a broad TCR affinity range. However, the extent to which such biophysical parameters contribute to T cell pathogenic potential remains unclear. In this study, we selected eight InsB9-23-specific TCRs cloned from CD4+ islet-infiltrating T cells that possessed a relatively broad range of TCR affinity to generate NOD TCR retrogenic mice. These TCRs exhibited a range of two-dimensional affinities (∼10-4-10-3 μm 4) that correlated with functional readouts and responsiveness to activation in vivo. Surprisingly, both higher and lower affinity TCRs could mediate potent insulitis and autoimmune diabetes, suggesting that TCR affinity does not exclusively dictate or correlate with diabetogenic potential. Both central and peripheral tolerance mechanisms selectively impinge on the diabetogenic potential of high-affinity TCRs, mitigating their pathogenicity. Thus, TCR affinity and multiple tolerance mechanisms converge to shape and broaden the diabetogenic T cell repertoire, potentially complicating efforts to induce broad, long-term tolerance.

Original languageEnglish (US)
Pages (from-to)571-579
Number of pages9
JournalJournal of Immunology
Volume193
Issue number2
DOIs
StatePublished - Jul 15 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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