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Requirement of CD28 signaling in homeostasis/survival of TGF-beta converted CD4+CD25+ Tregs from thymic CD4+CD25- single positive T cells



Requirement of CD28 signaling in homeostasis/survival of TGF-beta converted CD4+CD25+ Tregs from thymic CD4+CD25- single positive T cells



Transplantation 82(7): 953-964



Background. The thymus is a major organ that generates "natural" CD4(+)CD25(+) T regulatory cells (Tregs). However, the detailed pathway(s) by which Tregs are developed remain a mystery. CD28-/- mice have profound decrease in Tregs, but the underlying molecular events remain largely undefined.Methods. CD4(+)CD25(-) thymocytes from wildtype and CD28-/- mice were cultured with T-cell receptor (TCR) and transforming growth factor (TGF)-beta stimulation to generate CD25(+) Tregs and their phenotype and function were studied in vitro and in vivo.Results. TGF-beta induced Foxp3 expression in thymic CD4(+)CD25(-) cells and converted them to CD25(+) Tregs. The converted Tregs expressed high levels of CD25, whereas the non-suppressive CD4(+) T cells from the control cultures expressed CD25(low). CD28-/- thymic CD4(+)CD25(-) cells showed transit lower levels of Foxp3 upon TCR and TGF-beta stimulation early in culture, but the defect in Foxp3 expression was restored to normal levels after 60-72 hr. Consequently, TGF-beta converted CD28-/- CD25(-) cells to CD25(+) Tregs that were indistinguishable from those of the wildtype mice. However, the total number of TGF-beta converted CD28-/- Tregs was significantly lower than that of wildtype mice. In vivo, TGF-beta converted CD28-/- CD25(+) Tregs were less viable than those from the wildtype mice. Importantly, TGF-beta induced alloantigen specific CD4(+)CD25(+) Tregs from thymic CD25(-)SP cells which also required CD28 to maintain their survival.Conclusions. TGF-beta and TCR co-stimulation converts thymic CD4(+)CD25(-) T cells into CD4+CD25+ Tregs by inducing Foxp3, and the contribution of CD28 stimulation to this process is mainly through maintaining survival of the induced Tregs.

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Accession: 012884549

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PMID: 17038912

DOI: 10.1097/01.tp.0000232330.46688.37


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