Developmental control of CD8+ T cell-avidity maturation in autoimmune diabetes

Bingye Han, Pau Serra, Jun Yamanouchi, Abdelaziz Amrani, John F. Elliott, Peter Dickie, Teresa P. Dilorenzo, Pere Santamaria

Research output: Contribution to journalArticle

90 Scopus citations

Abstract

The progression of immune responses is generally associated with an increase in the overall avidity of antigen-specific T cell populations for peptide-MHC. This is thought to result from preferential expansion of high-avidity clonotypes at the expense of their low-avidity counterparts. Since T cell antigen-receptor genes do not mutate, it is puzzling that high-avidity clonotypes do not predominate from the outset. Here we provide a developmental basis for this phenomenon in the context of autoimmunity. We have carried out comprehensive studies of the diabetogenic CD8+ T cell population that targets residues 206-214 of the β cell antigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP206-214) and undergoes avidity maturation as disease progresses. We find that the succession of IGRP206-214-specific clonotypes with increasing avidities during the progression of islet inflammation to overt diabetes in nonobese diabetic mice is fueled by autoimmune inflammation but opposed by systemic tolerance. As expected, naive high-avidity IGRP206-214- specific T cells respond more efficiently to antigen and are significantly more diabetogenic than their intermediate- or low-avidity counterparts. However, central and peripheral tolerance selectively limit the contribution of these high-avidity T cells to the earliest stages of disease without abrogating their ability to progressively accumulate in inflamed islets and kill β cells. These results illustrate the way in which incomplete deletion of autoreactive T cell populations of relatively high avidity can contribute to the development of pathogenic autoimmunity in the periphery.

Original languageEnglish (US)
Pages (from-to)1879-1887
Number of pages9
JournalJournal of Clinical Investigation
Volume115
Issue number7
DOIs
StatePublished - Jul 1 2005

ASJC Scopus subject areas

  • Medicine(all)

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    Han, B., Serra, P., Yamanouchi, J., Amrani, A., Elliott, J. F., Dickie, P., Dilorenzo, T. P., & Santamaria, P. (2005). Developmental control of CD8+ T cell-avidity maturation in autoimmune diabetes. Journal of Clinical Investigation, 115(7), 1879-1887. https://doi.org/10.1172/JCI24219