A two-step process for thymic regulatory T cell development.
Recognition of self-antigens is required for regulatory T (Treg) cells to exert dominant tolerance. However, the mechanism by which self-reactive thymocytes are diverted into the Treg cell subset is unclear. To address this question, we looked for the immediate precursors to Treg cells within Foxp3(-)CD4+CD8(-) thymocytes. By using intrathymic transfer, we found that the CD25hi subset is highly enriched in Treg cell precursors. This was supported by tracking of thymocyte development via analysis of T cell receptor (TCR) repertoires in a TCR-beta transgenic model. These Treg cell precursors exist at a developmental stage where they are poised to express Foxp3 without further TCR engagement, requiring only stimulation by interleukin-2 (IL-2) or IL-15. Thus, we propose that the selection of self-reactive thymocytes into the Treg cell subset occurs via an instructive rather than stochastic-selective model whereby TCR signals result in the expression of proximal IL-2 signaling components facilitating cytokine-mediated induction of Foxp3.
Lio
Chan-Wang Joaquim
CW
Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Hsieh
Chyi-Song
CS
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000276:immunology / Q000378:metabolism; D017634:Self Tolerance / Q000276:immunology*; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; 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; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D011948:Receptors, Antigen, T-Cell; D050799:STAT5 Transcription Factor