IL-6 receptor blockade corrects defects of XIAP-deficient regulatory T cells.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29386580.
- Also identified by DOI 10.1038/s41467-018-02862-4 and PMC identifier 5792625.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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<sup>-/-</sup> regulatory T (Treg) cells and human XIAP-deficient Treg cells are defective in suppressive function. The Xiap<sup>-/-</sup> Treg cell defect is linked partly to decreased SOCS1 expression. XIAP binds SOCS1 and promotes SOCS1 stabilization. Foxp3 stability is reduced in Xiap<sup>-/-</sup> Treg cells. In addition, Xiap<sup>-/-</sup> Treg cells are prone to IFN-γ secretion. Transfer of wild-type Treg cells partly rescues infection-induced inflammation in Xiap<sup>-/-</sup> mice. Notably, inflammation-induced reprogramming of Xiap<sup>-/-</sup> Treg cells can be prevented by blockade of the IL-6 receptor (IL-6R), and a combination of anti-IL-6R and Xiap<sup>-/-</sup> Treg cells confers survival to inflammatory infection in Xiap<sup>-/-</sup> 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.
Medical subject headings
- Genetic Diseases, X-Linked
- Lymphoproliferative Disorders
- Receptors, Interleukin-6
- T-Lymphocytes, Regulatory