Intact regulatory T-Cell function but defective generation of IL-17A-producing CD4⁺ T cells in XIAP deficiency

Objective: X-linked inhibitor of apoptosis (xIAP) deficiency is a primary immune deficiency disorder associated with hemophagocytic lymphohistiocytosis. About 17% of xIAP-deficient patients present with very early onset severe colitis with high mortality. We hypothesized that xIAP deficiency leads to defective generation and/or survival of T regulatory cells (T_reg) through its involvement in transforming growth factor-b signaling. Methods and Results: We used a T-cell transfer model of chronic colitis and observed a mild increase in colitis severity induced by naïve CD4⁺ T cells from xIAP^0/- mice compared with colitis induced by naïve CD4⁺ T cells from WT mice. We did not observe any significant difference in the induction of T_reg cells in these studies. We next tested whether xIAP is required for T_reg cell function by co-transferring xIAP^-/0 or WT T_reg cells with naïve WTCD4 cells in this model. We demonstrate that XIAP-deficient T_reg cells were able to prevent disease similarly to WT T_reg cells. In these experiments we, however, found a significantly decreased percentage of IL- 17A-producing CD4⁺ T cells in mice receiving T_regs from xIAP^0/- mice. Conclusions: xIAP appears dispensable for the generation of induced T_reg cells as well as function of natural T_reg cells. There appeared to be a role of xIAP in generation of IL-17-producing cells from either naïve CD4⁺ T cells or T_reg cells. Further research is needed to explore the role of xIAP in generation of IL-17-producing cells.