IL-17 production elicited by allo-major histocompatibility complex class II recognition depends on CD25posCD4pos T cells.

Background. Interleukin (IL)-17 is involved in autoimmune inflammatory disorders and naturally occurring CD25(pos) regulatory T cells were shown to promote IL-17 synthesis. Because IL-17 is overproduced in certain types of allograft rejection, it is important to characterize the cells responsible for IL-17 synthesis and to define how IL-17 is regulated during alloimmune responses. Methods. Splenic CD4(pos) T cells were isolated from C57BL/6 mice and fractionated according to CD25 expression. T cells were stimulated by major histocompatibility complex class II-mismatched bone marrow-derived dendritic cells from bm12 mice, either immature or made mature by exposure to lipopolysaccharide. To track T cell populations, CD25(neg)CD4(pos) and CD25(pos)CD4(pos) were isolated from Thy1.1 and congenic Thy1.2 mice, respectively. Cell proliferation was quantified by CFSE dilution. IL-17-producing cells and FOXP3(pos) cells were enumerated by intracytoplasmic staining and cytokine levels in culture supernatants were measured by ELISA. Results. Addition of CD25(pos)CD4(pos) T cells to CD25(neg)CD(pos)) T cells inhibited IL-2, interferon-gamma, and IL-13 production but promoted IL-17 synthesis on stimulation by allogenic immature DC. In this setting, IL-17 originated from CD25(int)CD4(pos)FOXP3(neg) memory T cells, which depend on IL-2 to produce IL-17. Alloreactive CD25(neg)CD4(pos) T cells were also induced to produce IL-17 when stimulated by mature DC in the presence of CD25(high)CD4(pos)FOXP3(pos) T cells. Conclusions. We conclude that (1) the cellular source of IL-17 during an antiallo major histocompatibility complex class 11 response depends on the maturation status of allogenic DC, (2) whereas suppressing Th1 and Th2 cytokine synthesis, naturally occurring regulatory T cells, allow IL-17 production by alloreactive CD4(pos) T cells.