Interleukin-21-producing c-Maf-expressing CD4+ T cells induce effector CD8+ T cells and enhance autoimmune inflammation in scurfy mice

Objective: FoxP3 induces Treg cells and prevents autoimmune diseases. However, the precise mechanisms of FoxP3 in the prevention of autoimmune diseases remain unknown. We undertook this study to determine the regulatory roles of FoxP3 in autoimmune inflammation by using FoxP3-mutant sf mice.

Methods: We characterized interleukin-21 (IL-21)- producing cells in sf mice. We examined the underlying mechanisms of enhanced IL-21 production in sf mouse CD4+ T cells. We examined the roles of IL-21 and CD8+ T cells in autoimmune inflammation in sf mice using IL-21 receptor (IL-21R)-deficient sf mice.

Results: IL-21-producing c-Maf+CD4+ T cells, which were distinct from Th17 cells, were increased in sf mice. Increased c-Maf expression was involved in enhanced IL-21 production in sf mouse CD4+ T cells. Experiments using bone marrow chimeric mice showed that lack of cell-extrinsic suppression by FoxP3+ Treg cells, but not cell-intrinsic defects in FoxP3 in sf mouse CD4+ T cells, was mainly involved in the development of IL-21-producing c-Maf+CD4+ T cells in sf mice. IL-21R deficiency prolonged survival and reduced multiorgan autoimmune inflammation in sf mice. Moreover, IL-21R deficiency decreased short-lived effector CD8+ T cells in the lung in sf mice. Furthermore, depletion of CD8+ T cells inhibited lung inflammation in sf mice, suggesting that CD8+ T cells are critical for inducing lung inflammation in sf mice.

Conclusion: Unique IL-21-producing c-Maf+ CD4+ T cells develop in the absence of FoxP3+ Treg cells, induce short-lived effector CD8+ T cells, and enhance multiorgan autoimmune inflammation in sf mice.