Naturally arising CD4⁺CD25⁺ regulatory T cells suppress the expansion of colitogenic CD4⁺CD44 ^highCD62L^- effector memory T cells

Naturally arising CD4⁺CD25⁺ regulatory T (T _R) 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 (T_EM) CD4⁺ cell-mediated colitis model induced by adoptive transfer of colitogenic CD4 ⁺CD44^highCD62L^- lamina propria (LP) T cells obtained from colitic CD4⁺CD45RB^high T cell-transferred mice, we have shown in the present study that CD4⁺CD25⁺ T_R cells are able not only to suppress the development of colitis, Th1 cytokine production, and the expansion of colitogenic LP CD4⁺ T_EM cells but also to expand these cells by themselves extensively in vivo. An in vitro coculture assay revealed that CD4⁺CD25⁺ T_R cells proliferated in the presence of IL-2-producing colitogenic LP CD4⁺ T_EM 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⁺ T _R cells and the their suppressive activity on colitogenic LP CD4 ⁺ T_EM cells.