Intact Regulatory T-Cell Function but Defective Generation of IL-17A-Producing CD4+ 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-beta signaling. Methods and Results: We used a T-cell transfer model of chronic colitis and observed a mild increase in colitis severity induced by naive CD4(+) T cells from xIAP(0/-) mice compared with colitis induced by naive 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 x/AP(-/0) or WT Treg cells with naive WT CD4(+) cells in this model. We demonstrate that XIAP-deficient T-reg cells were able to prevent disease similarly to WT Treg 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 Treg cells. There appeared to be a role of xIAP in generation of IL-17-producing cells from either naive CD4(+) T cells or T-reg cells. Further research is needed to explore the role of xIAP in generation of IL-17-producing cells.