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

2010; American Association of Immunologists; Volume: 185; Issue: 7 Linguagem: Inglês

10.4049/jimmunol.1001281

1550-6606

Santiago Zelenay, Marie‐Louise Bergman, Ricardo Paiva, Andreia C. Lino, Ana C. Martins, João H. Duarte, Maria Francisca Moraes‐Fontes, Angelina M. Bilate, Juan J. Lafaille, Jocelyne Demengeot,

Immunotherapy and Immune Responses

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.