title: 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.
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal. Santiago.Zelenay@cancer.org.uk
authors.forename: Santiago
authors.initials: S
authors.lastname: Zelenay
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Bergman
authors.forename: Ricardo Sousa
authors.initials: RS
authors.lastname: Paiva
authors.forename: Andreia C
authors.initials: AC
authors.lastname: Lino
authors.forename: Ana C
authors.initials: AC
authors.lastname: Martins
authors.forename: João H
authors.initials: JH
authors.lastname: Duarte
authors.forename: Maria F
authors.initials: MF
authors.lastname: Moraes-Fontes
authors.forename: Angelina M
authors.initials: AM
authors.lastname: Bilate
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Lafaille
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Demengeot
mesh_terms: 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
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015850:Interleukin-6