(755) Manganese mitigates aGVHD by promoting allogenic T cell exhaustion

Introduction/Rationale: Acute graft-versus-host disease (aGVHD) is one of the major complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is mediated by donor T cells in response to alloantigen presented by MHC-I and MHC-II on antigen-presenting cells. Recent studies have demonstrated that STING is involved in aGVHD pathogenesis. However, therapies targeting cGAS/STING signal in allogenic response remains unclear.

Methods: To establish murine aGVHD model, lethally irradiated BALB/C (H-2d) recipients were injected intravenously with 1×10^7 bone marrow (BM) cells and 5×10^6 splenocytes from C57BL/6 (H-2b) donors. Recipients were intravenously injected with 5 mg/kg manganese once a day 1 days prior to BMT for a period of one week. To explore the potential mechanisms of manganese in the regulation of aGVHD, we profiled the immune cell responses in splenocytes by flow cytometry 2 weeks post transplantation. scRNA-seq and scATAC-seq were performed to dissect the potential mechanisms.

Results: cGAS/STING agonists manganese significantly mitigates aGVHD development and represses donor T cell activation. scRNA-seq showed that manganese inhibits neutrophil infiltration and antigen presentation by activation of type I interferon signal. Interestingly, manganese treatment down-regulates stem-like gene expression patterns, whilst up-regulates exhaustion related genes expression. Flow cytometry analysis showed manganese inhibits both progenitor and KLRG1+ effector T cell populations, and further permits T cell terminal exhaustion. scATAC-seq were performed to dissect the epigenetic regulation of T cell exhaustion program.

Conclusion: In sum, we demonstrated that STING agonists manganese limits neutrophil antigen presentation through type I interferon and permits allo-reactive T cell exhaustion, thereby mitigating aGVHD development.