CD137 and IFN-γ signaling in mature cDC2Bs play a central role in the regulatory feedback mechanism for alloimmune responses 2328469

Abstract

Abstract Introduction Conventional dendritic cells (cDCs) are a prototype of professional antigen-presenting cells that dictate T-cell activation and differentiation: however, the function of post-primed cDCs is yet to be clarified. Here, we report the identification of a mature subset of type 2 cDCs (cDC2s) capable of suppressing alloimmune responses. Methods Donor BM12(H2-Ab1bm12) or Balb/c splenocytes/lymphocytes (8x10^7) were transfered to C57BL/6 or CBF1 recipients to induce chronic GVHD or acute GVHD, respectively. Various immunological tools were used to analyze immune responses. Results In autoantibody-mediated chronic graft-versus-host disease (GVHD) models, Tnfrsf9 deficiency in recipients resulted in a dysregulation of FCGR1+FCGR2B+CLEC12A+ splenic cDC2Bs, leading to uncontrolled type 1 alloimmune responses. By contrast, engagement of CD137 (encoded by Tnfrsf9) reenforced the immunoregulatory capacity of these inflammatory cDC2Bs in such a way that they suppressed type 2 as well as type 1 alloimmune responses. Mechanically, AHR induced by CD137 signaling suppressed IFN-γ-stimulated genes (e.g., Il12a) by repressing STAT1 transcriptional activation, while upregulating immunoregulatory genes (e.g., Il10) in cooperation with STAT1. IFN-γ promoted production of IL-12 and deletion of donor Treg cells in Tnfrsf9-/- recipients. Conclusion Taken together, this study identifies CD137 signaling in mature cDC2Bs as a master switch for negative feedback regulation mediated by IFN-γ to restrict type 1 alloimmunity-induced systemic inflammation. Funding Source National Research Foundation of Korea (NRF), Republic of Korea Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)