IL-27 promotes IL-10-producing T cell differentiation through induction of AhR and c-Maf, and enhances IL-10 production in various T cell subsets resulting in the conversion of effector T cells into T regulatory type 1 (Tr1)-like cells. Recently, B lymphocyte-induced maturation protein-1 (Blimp-1) has been demonstrated to play an important role in IL-10 production from Tr1 cells. However, how the reciprocal regulation between c-Maf and Blimp-1 mediates IL-27-induced IL-10 expression and modulates the colitogenicity of T cells is still unclear. To pursue this critical issue, we knocked down IL-27 by introducing a shRNA transgene to target the p28 subunit in T cell-specific Blimp-1 knockout (CKO) mice and examined the severity of disease in these CKO/IL-27p28 knockdown (KD) mice. The onset of weight loss and diarrhea in CKO/IL-27p28 KD mice was observed at earlier age than CKO mice. Although IFN-g and IL-17 levels of CD4 + T cells were downregulated, IL-10 expression in Th1 cells was significantly lower in the lymphoid organs of CKO/IL-27p28 KD mice. To further investigate the effect of c-Maf on the pathogenesis of Blimp-1 deficiency-mediated colitis, we crossed T cell-specific c-Maf transgenic mice with CKO mice. The onset of colitis in these mice was delayed. The Th1 and Th17 populations were increased whereas the population of IL-10-producing CD4 + T cells from lymphoid organs of CKO/c-Maf mice were higher than those of CKO mice. In conclusion, the reciprocal regulation between c-Maf and Blimp-1 in IL-27-dependent IL-10 expression is essential for modulating the colitogenicity of T cells to maintain intestinal homeostasis.
Date:
2019-10
Relation:
European Journal of Immunology. 2019 Oct;49(S3):849.
