Cutting edge: Intrathymic differentiation of adaptive Foxp3+ regulatory T cells upon peripheral proinflammatory immunization.
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.
Zelenay
Santiago
S
Instituto Gulbenkian de Ciência, Oeiras, Portugal. Santiago.Zelenay@cancer.org.uk
Bergman
Marie-Louise
ML
Paiva
Ricardo Sousa
RS
Lino
Andreia C
AC
Martins
Ana C
AC
Duarte
João H
JH
Moraes-Fontes
Maria F
MF
Bilate
Angelina M
AM
Lafaille
Juan J
JJ
Demengeot
Jocelyne
J
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology; D007114:Immunization; D007249:Inflammation / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015850:Interleukin-6