IFNGR/STAT1 signaling in recipient hematopoietic antigen presenting cells suppresses graft-versus-host disease
The Journal of clinical investigation
Antigen-presenting cells; Bone marrow transplantation; Immunology; Tolerance; Transplantation
Absence of Interferon-γ Receptor (IFNGR) or Signal Transducer and Activator of Transcription 1 (STAT1) signaling in donor cells has been shown to result in reduced acute GVHD induction. In this study, we unexpectedly observed increased activation and expansion of donor lymphocytes in both lymphohematopoietic organs and GVHD target tissues of IFNGR/STAT1-deficient recipient mice, leading to rapid mortality following the induction of GVHD. Lipopolysaccharide (LPS)-matured bone marrow-derived Ifngr1-/-/Stat1-/- dendritic cells (BMDCs) were more potent allogeneic stimulators and expressed increased levels of MHC II and costimulatory molecules. Similar effects were observed in human APCs with knockdown of Stat1 by CRISPR/Cas9 and treatment with a JAK1/2 inhibitor. Furthermore, we demonstrated that the absence of IFNGR/STAT1 signaling in hematopoietic APCs impaired the presentation of exogenous antigens while promoting the presentation of endogenous antigens. In contrast, the indirect presentation of host antigens to donor lymphocytes was defective in IFNGR/STAT1-deficient donor-derived APCs in fully donor chimeric mice. The differential effects of IFNGR/STAT1 signaling on endogenous and exogenous antigen presentation could provide further insight into the roles of the IFN-γ/STAT1 signal pathway in the pathogenesis of GVHD, organ rejection, and autoimmune diseases.
Lu, Caisheng; Ma, Huihui; Song, Liangsong; Wang, Hui; Wang, Lily; Li, Shirong; Lagana, Stephen M.; Sepulveda, Antonia R.; Hoebe, Kasper; Pan, Samuel S.; Yang, Yong-Guang; Lentzsch, Suzanne; and Mapara, Markus Y., "IFNGR/STAT1 signaling in recipient hematopoietic antigen presenting cells suppresses graft-versus-host disease" (2022). GW Authored Works. Paper 1888.