By Kurt Blaser, Johannes Ring, Monique Capron, Judah A. Denburg, Stephen T. Holgate
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Additional resources for T Cell Regulation in Allergy, Asthma and Atopic Skin Diseases (Chemical Immunology)
2) [53–55]. An evolutionary conserved Foxp3 enhancer that binds NFAT and Smad3, allowing responsiveness to TCR and TGF-␤ signaling, respectively . Concerted action of NFAT and Smad3 is required for histone H4 acetylation of the enhancer region and for Foxp3 induction. TGF-␤ is important for induction of iTR cells and for the maintenance of TR cells in the periphery, but is dispensable for the induction of nTR cells in the thymus . Molecular Mechanisms of Regulatory T-Cell Development Whether alternative pathways of Smad3 activation occur in developing nTR cells the thymus (through the agency of activins or bone morphogenic proteins), or whether Smad3-independent pathways of Foxp3 induction are operative the thymus remains to be established.
Nat Immunol 2008;9:194–202. 57 Marie JC, Letterio JJ, Gavin M, Rudensky AY: TGF-␤1 maintains suppressor function and Foxp3 expression in CD4ϩCD25ϩ regulatory T cells. J Exp Med 2005;201:1061–1067. 58 Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM: Conversion of peripheral CD4ϩCD25Ϫ naive T cells to CD4ϩCD25ϩ regulatory T cells by TGF-␤ induction of transcription factor Foxp3. J Exp Med 2003;198:1875–1886. 59 Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF: Cutting edge: TGF-␤ induces a regulatory phenotype in CD4ϩCD25Ϫ T cells through Foxp3 induction and downregulation of Smad7.
CD4ϩ CD25ϩTR cells produce TGF-␤ and IL-10, two cytokines endowed with immunosuppressive functions and which play critical functions in TR cell biology. The majority of peripheral TR cells are programmed in the thymus and are known as natural TR (nTR) cells . Other TR cells known as induced or adaptive (iTR) cells are derived de novo from a naive CD4ϩ precursor pool in peripheral lymphoid tissues after encountering exogenous antigen under the influence of TGF-␤. Intense effort has gone into defining the molecular events that guide TR cells through development and lineage commitment, and those that enable the acquisition and maintenance of TR cell phenotypic and functional attributes.