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 1

Absence of host IFN-γR/STAT1 signaling enhances GVHD induction.

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Absence of host IFN-γR/STAT1 signaling enhances GVHD induction. GVHD was...
GVHD was induced in the fully MHC-mismatched [BALB/c (H2d) to 129Sv (H2b)] strain combination. SYN, syngeneic transplant. (A) Lethally irradiated (1,044 cGy) 129.Stat1–/– or 129.Stat1+/+ mice received 5 × 106 BMCs and 1 × 107 SPCs from BALB/c mice. Data are from 2 similar experiments with 12–14 animals/group. (B and C) CD25 expression (B) and intracellular IFN-γ expression (C) on donor (H2Dd) CD4+ or CD8+ T cells in the host spleen were tested on day 4 after BMT. Representative results from 1 of 2 independent experiments with 3–4 animals/group are shown. (D) In vivo expansion of alloreactive donor BALB/c-Luc T cells and target organ infiltration in B6.WT or Stat1–/– recipients were assessed by BLI on post-BMT day 6. Representative results from 1 of 3 independent experiments with 3–4 animals per group are shown. (E–H) Fully MHC-mismatched GVHD induction following lethal irradiation in B6 (WT, n = 5) versus B6.Ifngr1–/– recipients (Ifngr1–/–, n = 8) using 1 × 107 SPCs and 5 × 106 BMCs from BALB/c-Luc mice. Survival data were analyzed by log-rank test. Activation of donor (H2d+) CD4+ T cells, CD8+ T cells, and lymphocytes and (F) intracellular IFN-γ staining of donor-derived CD4+ T cells (G) was tested on day 4 after BMT. (H) Recipient animals were monitored for infiltration and expansion of BALB/c-Luc lymphocytes on day 7 after BMT using BLI. Representative results from 1 of 2 independent experiments with 3–4 animals/group are shown. Bar graphs represent the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by log-rank test (A), 2-way ANOVA with Šidák’s correction (B–F and H), and Student’s t test (G).