SOCS3 knockout of donor transplanted cells exacerbates GVHD associated with a high-fat diet in murine allogeneic HSCT

Suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling that are required to prevent excessive cellular responses. SOCS3 suppresses inflammation caused by metabolic stress, and a high-fat diet (HFD) accelerates the progression of systemic inflammation in systemic SOCS3 knockout (KO) mice via severe granulopoiesis. An HFD induces metabolic stress and chronic low-grade inflammation, contributing to graft-versus-host disease (GVHD) severity. We investigated the effects of SOCS3 deficiency in donor cells and HFD administration to recipients on the development of GVHD. Transplantation involving a wild-type (WT) donor and a recipient fed with an HFD resulted in skin and colon GVHD and shortened median survival time. Transplantation involving an SOCS3 KO donor and a recipient fed with an HFD exacerbated GVHD via increased CD4 and CD8 effector memory T cell ratios. Splenocytes after hematopoietic stem cell transplantation also showed high expression of CD49d, CD62L, and CD25 in CD4 + T cells and low expression of programmed cell death protein 1 and CD69 in CD8 + T cells. Analysis of recipient spleen cells 30 days after transplantation revealed higher interleukin-6 expression in groups receiving transplants from SOCS3 KO donors fed with a control diet or a HFD, compared with the group receiving transplants from WT donors fed a control diet. These results suggest that SOCS3 suppresses HFD-induced GVHD.