IL-6 receptor blockade corrects defects of XIAP-deficient regulatory T cells

X-linked lymphoproliferative syndrome type-2 (XLP-2) is a primary immunodeficiency disease attributed to XIAP mutation and is triggered by infection. Here, we show that mouse Xiap(−/−) regulatory T (Treg) cells and human XIAP-deficient Treg cells are defective in suppressive function. The Xiap(−/−) Treg cell defect is linked partly to decreased SOCS1 expression. XIAP binds SOCS1 and promotes SOCS1 stabilization. Foxp3 stability is reduced in Xiap(−/−) Treg cells. In addition, Xiap(−/−) Treg cells are prone to IFN-γ secretion. Transfer of wild-type Treg cells partly rescues infection-induced inflammation in Xiap(−/−) mice. Notably, inflammation-induced reprogramming of Xiap(−/−) Treg cells can be prevented by blockade of the IL-6 receptor (IL-6R), and a combination of anti-IL-6R and Xiap(−/−) Treg cells confers survival to inflammatory infection in Xiap(−/−) mice. Our results suggest that XLP-2 can be corrected by combination treatment with autologous iTreg (induced Treg) cells and anti-IL-6R antibody, bypassing the necessity to transduce Treg cells with XIAP.