IFN-γR/STAT1 signaling in recipient hematopoietic antigen-presenting cells suppresses graft-versus-host disease
Caisheng Lu, … , Suzanne Lentzsch, Markus Y. Mapara
Caisheng Lu, … , Suzanne Lentzsch, Markus Y. Mapara
Published November 29, 2022
Citation Information: J Clin Invest. 2023;133(3):e125986. https://doi.org/10.1172/JCI125986.
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Research Article Immunology

IFN-γR/STAT1 signaling in recipient hematopoietic antigen-presenting cells suppresses graft-versus-host disease

Abstract

The absence of IFN-γ receptor (IFN-γR) or STAT1 signaling in donor cells has been shown to result in reduced induction of acute graft-versus-host disease (GVHD). In this study, we unexpectedly observed increased activation and expansion of donor lymphocytes in both lymphohematopoietic organs and GVHD target tissues of IFN-γR/STAT1–deficient recipient mice, leading to rapid mortality following the induction of GVHD. LPS-matured, BM-derived Ifngr1–/– Stat1–/– DCs (BMDCs) were more potent allogeneic stimulators and expressed increased levels of MHC II and costimulatory molecules. Similar effects were observed in human antigen-presenting cells (APCs) with knockdown of Stat1 by CRISPR/Cas9 and treatment with a JAK1/2 inhibitor. Furthermore, we demonstrated that the absence of IFN-γR/STAT1 signaling in hematopoietic APCs impaired the presentation of exogenous antigens, while promoting the presentation of endogenous antigens. Thus, the indirect presentation of host antigens to donor lymphocytes was defective in IFN-γR/STAT1–deficient, donor-derived APCs in fully donor chimeric mice. The differential effects of IFN-γR/STAT1 signaling on endogenous and exogenous antigen presentation could provide further insight into the roles of the IFN-γ/STAT1 signaling pathway in the pathogenesis of GVHD, organ rejection, and autoimmune diseases.

Authors

Caisheng Lu, Huihui Ma, Liangsong Song, Hui Wang, Lily Wang, Shirong Li, Stephen M. Lagana, Antonia R. Sepulveda, Kasper Hoebe, Samuel S. Pan, Yong-Guang Yang, Suzanne Lentzsch, Markus Y. Mapara

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Figure 2

Contribution of hematopoietic versus nonhematopoietic IFN-γR/STAT1 deficiency to the development of GVHD.

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Contribution of hematopoietic versus nonhematopoietic IFN-γR/STAT1 defic...
(A and B) GVHD was induced in radiation chimeras with STAT1 deficiency in the hematopoietic compartment (129.Stat1–/–→129.Stat1+/+). The data are representative of 2 similar experiments with 9–12 mice/group. (A) MST was 6 days versus 11 days (P = 0.02, log-rank test). (B) CD25 expression on donor (H-2d) CD4+ and CD8+ T cells was assessed on day 6 after BMT. (C) Donor lymphocyte activation was assessed in chimeric mice with STAT1 deficiency restricted to nonhematopoietic cells using B6.Stat1Poison mice. Lethally irradiated (1,075 cGy) B6.Stat1Poison mice or B6 WT mice received 5 × 106 BMCs from B6.SJL syngeneic WT mice. Four months after the first transplantation, the chimeras were irradiated (1,075 cGy) and injected with 5 × 106 BMCs and 1 × 107 splenocytes from BALB/c mice. CD25 expression on donor (H-2d) CD4+ and CD8+ T cells was measured on day 7 after BMT (n = 5 mice/group). (D–F) GVHD induction in irradiated chimeras with IFN-γR deficiency in the hematopoietic (B6.Ifngr1–/–→B6.SJL) (D and E) and nonhematopoietic compartments (B6.SJL→B6.Ifngr1–/–) (F). (D) Probability of survival (MST of 9.5 days vs. 43 days, log-rank test *P < 0.05, n = 3–6 mice/group). (E) In vivo expansion of BALB/c-Luc lymphocytes in recipient animals was monitored using BLI on the indicated days after the second transplantation. (F) Survival curve following GVHD induction in Ifngr1–/–→Ifngr1–/– chimeras with BALB/c splenic cells (MST of 15 days vs. 9 days, log-rank test P < 0.05, n = 5–6 mice/group). Bar graphs represent the mean ± SEM. *P < 0.05 and ***P < 0.001, by 2-way ANOVA with Šidák’s correction.