Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-02862-4
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Funding
- Ministry of Science and Education (Taiwan, R.O.C.) [MOST 105-2321-B-001-065]
- Academia Sinica Investigator Award from Academia Sinica, Taiwan, R.O.C.
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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-gamma 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-IL6R antibody, bypassing the necessity to transduce Treg cells with XIAP.
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