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 Transplantation

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 4

Absence of IFN-γR/STAT1 signaling leads to enhanced endogenous and compromised exogenous antigen presentation.

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Absence of IFN-γR/STAT1 signaling leads to enhanced endogenous and compr...
(A) GVHD was induced in the parent-into-F1 (P→F1) mouse model without irradiation. CB6F1 (H2bd) WT or Ifngr1–/– mice received 5 × 106 BMCs and 2.5 × 107 to 3 × 107 splenocytes from B6.SJL mice. There was an increase in I-Ab expression and recipient-derived endogenous Ea52-68 peptide presentation (tested by Y-Ae staining) on CD11c+ cells on day 2 after BMT. Data are representative of 2 similar experiments with 5 animals/group. (B and C) OT-II T cell proliferation was determined by CFSE dilution in response to 3 days of stimulation with 0.5% PFA-fixed B6.Ifngr1–/– or Stat1–/– BMDCs. BMDCs were incubated for 1 hour with OVA (100 ng/mL) and then overnight in the presence of LPS. For OVA323–339 peptide loading, BMDCs were matured with LPS, fixed with 0.5% PFA, and then pulsed with 100 ng/mL OVA323–339 peptides for 0.5 hours. (D) OT-II proliferation in response to 3 days of stimulation with WT act-mOVA (OVA-B6) or Stat1–/– act-mOVA (OVA-Stat1–/–) BMDCs after overnight LPS maturation. WT and Stat1–/– BMDCs without constitutive OVA expression were used as controls. (E and F) OVA-B6 or OVA-Stat1–/– mice were lethally irradiated (10.75 Gy) and received 3 × 106 splenocytes from OTII mice. CD25 and IFN-γ expression was detected in OT-II cells 5 days after injection. n = 2–3 mice/group. F shows summary data for E. Bar graphs in A, E, and F represent the mean ± SEM. *P < 0.05 and **P < 0.01, by 2-tailed Student’s t test. Max, maximum.