期刊
JOURNAL OF IMMUNOLOGY
卷 193, 期 11, 页码 5525-5533出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1402144
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资金
- Medical Research Council (U.K.) [U117573801]
- MRC [MC_U117573801, MC_PC_13055] Funding Source: UKRI
- Medical Research Council [MC_PC_13055, MC_U117573801] Funding Source: researchfish
The developmental pathways of regulatory T cells (T-reg) generation in the thymus are not fully understood. In this study, we reconstituted thymic development of Zap70-deficient thymocytes with a tetracycline-inducible Zap70 transgene to allow temporal dissection of Treg development. We find that T-reg develop with distinctive kinetics, first appearing by day 4 among CD4 single-positive (SP) thymocytes. Accepted models of CD25(+)Foxp3(+) T-reg selection suggest development via CD25(+)Foxp3(-) CD4 SP precursors. In contrast, our kinetic analysis revealed the presence of abundant CD25(-)Foxp3(+) cells that are highly efficient at maturing to CD25(+)Foxp3(+) cells in response to IL-2. CD25(-)Foxp3(+) cells more closely resembled mature T-reg both with respect to kinetics of development and avidity for self-peptide MHC. These population also exhibited distinct requirements for cytokines during their development. CD25(-)Foxp3(+) cells were IL-15 dependent, whereas generation of CD25(+)Foxp3(+) specifically required IL-2. Finally, we found that IL-2 and IL-15 arose from distinct sources in vivo. IL-15 was of stromal origin, whereas IL-2 was of exclusively from hemopoetic cells that depended on intact CD4 lineage development but not either Ag-experienced or NKT cells.
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