Auto-reactive exTreg cells are generated during the initiation of autoimmune inflammation. (115.23)

Abstract

Abstract The onset of autoimmunity is associated with a reduced frequency of Foxp3+ T regulatory (Treg) cells, or reduced Foxp3 expression. We have observed that Tregs can lose Foxp3 under homeostatic conditions to form exTreg cells, and that islet-specific exTreg cells induced autoimmune type 1 diabetes (T1D). ExTreg generation in the islets correlates with low IL-2Rα (CD25) expression, and IL-2 complexes directed at Treg cells can rescue T1D. Unstable Foxp3 expression may weaken the ability of the Treg compartment to suppress effectors, and, exTregs can themselves be pathogenic. In this study, we used class II tetramers conjugated with myelin oligodendrocyte peptide 38-49 (MOG38-49) to analyze the myelin-reactive potentially pathogenic CD4+ conventional effector T cells and Treg cells during experimental autoimmune encephalomyelitis (EAE). We observed exTreg generation from Tregs enriched for MOG38-49-specificity, and this correlated with EAE progression. CD25 expression was high on Tregs and exTregs in the inflamed central nervous system, so low CD25 cannot explain Foxp3 instability in this setting. This is the first description of auto-reactive Treg cells within a normal T cell repertoire losing Foxp3 expression during the onset of autoimmunity. It supports the hypothesis that Tregs are enriched for self-reactivity, and that unstable Tregs are associated with progressive autoimmune disease.