Cutting Edge: Intrathymic Differentiation of Adaptive Foxp3+ Regulatory T Cells upon Peripheral Proinflammatory Immunization

Abstract

Thymocytes differentiate into CD4⁺ Foxp3⁺ regulatory T cells (T_R) upon interaction between their TCR and peptide–MHC II complexes locally expressed in the thymus. Conversion of naive CD4⁺ T cells into T_R can additionally take place in the periphery under noninflammatory conditions of Ag encounter. In this study, making use of TCR transgenic models naturally devoid of Foxp3⁺ cells, we report de novo generation of T_R upon a single footpad injection of Ag mixed with a classic proinflammatory adjuvant. Abrupt T_R differentiation upon immunization occurred intrathymically and was essential for robust tolerance induction in a mouse model of spontaneous encephalomyelitis. This phenomenon could be attributed to a specific feature of thymocytes, which, in contrast to mature peripheral CD4⁺ T cells, were insensitive to the inhibitory effects of IL-6 on the induction of Foxp3 expression. Our findings uncover a pathway for T_R generation with major implications for immunity and tolerance induction.