CD4(+)CD25(+) T-cell development is regulated by at least 2 distinct mechanisms.

It has recently been shown that CD4(+)CD25(+) T cells are immunoregulatory T cells that prevent CD4(+) T-cell-mediated organ-specific autoimmune diseases. In this study, the regulatory mechanism of CD4(+)CD25(+) T-cell development were investigated using T-cell receptor (TCR) transgenic mice. It was found that CD4(+)CD25(+) T cells preferentially expressed the endogenous TCRalpha chain in DO10(+) TCR transgenic mice compared with CD4(+)CD25(-) T cells. Moreover, it was found that CD4(+)CD25(+) thymocytes were severely decreased in DO10(+) TCR-alpha(-/-) mice in positively selecting and negatively selecting backgrounds, whereas CD4(+)CD25(-) thymocytes efficiently developed by transgenic TCR in DO10(+) TCR-alpha(-/-) mice in positively selecting backgrounds, indicating that the appropriate affinity of TCR to major histocompatibility complex (MHC) for the development of CD4(+)CD25(+) thymocytes is different from that of CD4(+)CD25(-) thymocytes and that a certain TCR-MHC affinity is required for the development of CD4(+)CD25(+) thymocytes. Finally, it was found that, in contrast to thymus, CD4(+)CD25(+) T cells were readily detected in spleen of DO10(+) TCR-alpha(-/-) mice in positively selecting backgrounds and that splenic CD4(+)CD25(+) T cells, but not CD4(+)CD25(+) thymocytes, were significantly decreased in B-cell-deficient mice, suggesting that B cells may control the peripheral pool of CD4(+)CD25(+) T cells. Together, these results indicate that the development of CD4(+)CD25(+) T cells in thymus and the homeostasis of CD4(+)CD25(+) T cells in periphery are regulated by distinct mechanisms.