Naturally arising CD4+CD25+ regulatory T cells suppress the expansion of colitogenic CD4+CD44highCD62L− effector memory T cells

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Abstract
Naturally arising CD4+CD25+ regulatory T (TR) cells have been shown to prevent and cure murine T cell-mediated colitis. However, their exact mechanism of controlling colitogenic memory CD4+ T cells in in vivo systems excluding the initial process of naive T cell activation and differentiation has not been examined to date. Using the colitogenic effector memory (TEM) CD4+ cell-mediated colitis model induced by adoptive transfer of colitogenic CD4+CD44highCD62L− lamina propria (LP) T cells obtained from colitic CD4+CD45RBhigh T cell-transferred mice, we have shown in the present study that CD4+CD25+ TR cells are able not only to suppress the development of colitis, Th1 cytokine production, and the expansion of colitogenic LP CD4+ TEM cells but also to expand these cells by themselves extensively in vivo. An in vitro coculture assay revealed that CD4+CD25+ TR cells proliferated in the presence of IL-2-producing colitogenic LP CD4+ TEM cells at the early time point (48 h after culture), followed by the acquisition of suppressive activity at the late time point (96 h after culture). Collectively, these data suggest the distinct timing of the IL-2-dependent expansion of CD4+CD25+ TR cells and the their suppressive activity on colitogenic LP CD4+ TEM cells.