Lack of IFN-γ Receptor Signaling Inhibits Graft-versus-Host Disease by Potentiating Regulatory T Cell Expansion and Conversion

• Published in: The Journal of immunology (1950) 2023-09, Vol.211 (5), p.885-894
• Main Authors: Zhai, Naicui, Liu, Wentao, Jin, Chun-Hui, Ding, Yanan, Sun, Liguang, Zhang, Donghui, Wang, Zhaowei, Tang, Yang, Zhao, Wenjie, LeGuern, Christian, Mapara, Markus Y, Wang, Hui, Yang, Yong-Guang
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.2200411

IFN-γ is a pleiotropic cytokine that plays a controversial role in regulatory T cell (Treg) activity. In this study, we sought to understand how IFN-γ receptor (IFN-γR) signaling affects donor Tregs following allogeneic hematopoietic cell transplant (allo-HCT), a potentially curative therapy for leukemia. We show that IFN-γR signaling inhibits Treg expansion and conversion of conventional T cells (Tcons) to peripheral Tregs in both mice and humans. Mice receiving IFN-γR-deficient allo-HCT showed markedly reduced graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects, a trend associated with increased frequencies of Tregs, compared with recipients of wild-type allo-HCT. In mice receiving Treg-depleted allo-HCT, IFN-γR deficiency-induced peripheral Treg conversion was effective in preventing persistent GVHD while minimally affecting GVL effects. Thus, impairing IFN-γR signaling in Tcons may offer a promising strategy for achieving GVL effects without refractory GVHD. Similarly, in a human PBMC-induced xenogeneic GVHD model, significant inhibition of GVHD and an increase in donor Tregs were observed in mice cotransferred with human CD4 T cells that were deleted of IFN-γR1 by CRISPR/Cas9 technology, providing proof-of-concept support for using IFN-γR-deficient T cells in clinical allo-HCT.