CD44 expression positively correlates with Foxp3 expression and suppressive function of CD4(+ )T(reg )cells

BACKGROUND: CD4(+)CD25(+ )regulatory T (T(reg)) cells develop in the thymus and can suppress T cell proliferation, modulated by Foxp3 and cytokines; however, the relevance of CD44 in T(reg )cell development is less clear. To address this issue, we analyzed Foxp3 expression in CD44(+ )T(reg )cells by using multiple parameters, measured the levels of the immunoregulatory cytokine interleukin (IL)-10 in various thymocyte subsets, and determined the suppressor activity in different splenic T(reg )cell populations. RESULTS: Within mouse thymocytes, we detected T(reg )cells with two novel phenotypes, namely the CD4(+)CD8(-)CD25(+)CD44(+ )and CD4(+)CD8(-)CD25(+)CD44(- )staining features. Additional multi-parameter analyses at the single-cell and molecular levels suggested to us that CD44 expression positively correlated with Foxp3 expression in thymocytes, the production of IL-10, and T(reg )activity in splenic CD4(+)CD25(+ )T cells. This suppressive effect of T(reg )cells on T cell proliferation could be blocked by using anti-IL-10 neutralizing antibodies. In addition, CD4(+)CD25(+)CD44(+ )T(reg )cells expressed higher levels of IL-10 and were more potent in suppressing effector T cell proliferation than were CD4(+)CD25(+)CD44(- )cells. CONCLUSION: This study indicates the presence of two novel phenotypes of T(reg )cells in the thymus, the functional relevance of CD44 in defining T(reg )cell subsets, and the role of both IL-10 and Foxp3 in modulating the function of T(reg )cells. REVIEWERS: This article was reviewed by Dr. M. Lenardo, Dr. L. Klein & G. Wirnsberger (nominated by Dr. JC Zungia-Pfluker), and Dr. E.M. Shevach.