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.
View: Text | PDF
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

×

Figure 5

APCs with deficient IFN-γR/STAT1 signaling exhibit increased direct and compromised indirect antigen presentation.

Options: View larger image (or click on image) Download as PowerPoint
APCs with deficient IFN-γR/STAT1 signaling exhibit increased direct and ...
(A) GVHD was induced in the P→F1 [B6.SJL(H2b)→CB6F1 (H2bxd)] mouse model using WT or Ifngr1–/– recipients, and GVHD-induced mortality was monitored. Ifngr1–/– F1 recipient mice exhibited significantly increased GVHD-induced mortality (MST of 32 days vs. not reached, log-rank test **P < 0.01, n = 5 mice/group). (B and C) Splenic T cell activation was determined by the percentage of CD62L–CD44+ donor T cells, and differentiation (Th1, Th17, and Treg) was assessed by IFN-γ, IL-17A, and FOXP3 expression in donor CD4+T cells on day 7 after BMT. n = 3 mice/group. (D and E) Donor-derived CD11c+ cells were assessed on day 18 after transplantation for MHC II (I-Ab) and associated Ea52-68 peptide presentation (Y-Ae expression) following fully MHC-mismatched BMT in BALB/c mice that received 5 × 106 TCD BMCs from either WT B6 or Stat1–/– mice after 8 Gy irradiation (n = 3 mice/group). (F–J) In vivo proliferation of TEa-TCR–Tg T cells specific for Ea52-68 peptide presented by I-Ab. Three weeks after transplantation, 5 × 106 CellTrace Violet–labeled pan–T cells from TEa-TCR–Tg mice were administered i.v. to B6.WT→BALB/c or B6.Stat1–/–→BALB/c chimeras. Proliferation was determined by CellTrace Violet dilution (F and G), activation (H), and Th1 differentiation (I) of antigen-specific TEa TCR+ donor T cells (CD4+Va2+Vb6+) on day 5 after DLI (n = 3 mice/group). (J) Clinical GVHD scores were recorded on day 7 after DLI of TEa-TCR–Tg T cells (n = 4 mice/group). Bar graphs represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-way ANOVA with Šidák’s correction (B and C) and 2-tailed Student’s t test (E and G–J).