Donor Deubiquitinase Otud1 Deficiency Attenuates The Severity Of Agvhd Mice After Allo-Hsct By Suppressing T Cell Activation And Expansion

Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important means to treat malignant diseases currently. However, the occurrence and development of acute graft versus host disease (aGVHD) seriously affect the survival and prognosis of patients. aGVHD is mainly mediated by the allogeneic immune response of activated donor T cells. Ubiquitination plays essential roles in T cell activation and is counteracted by multiple deubiquitinases (DUBs) with poorly understood. Here we show that OTUD1 deficiency negatively regulates the activation and effector function of naïve CD4+ T cells in vitro, and the proliferation of CD4+ T cells was also suppressed. Moreover, we found that OTUD1-deficient donor CD4+ T cells proliferates less in recipients compared to OTUD1+/+CD4+ T cells transferred. Interestingly, we found that OTUD1 expression was up-regulated in allo-HSCT mice when compared with syngeneic hematopoietic stem cell transplantation (syn-HSCT) mice. We further documented donor OTUD1 deficiency significantly prolongs the survival of aGVHD mice, and decreases the aGVHD scores. Moreover, OTUD1-deficient donor CD4+ T cells also attenuate the severity of aGVHD mice. Associated mechanistic studies revealed that the frequency and activation of CD4+ T cells were significantly reduced in recipients receiving OTUD1−/− bone marrow (BM) cells and splenocytes compared to those transferred OTUD1+/+ BM cells and splenocytes. Furthermore, overexpression of OTUD1 promotes NFAT-luciferase activity and up-regulates CD3-TCR complex stability. These results yield that targeting OTUD1 to regulate T cell-mediated allogeneic responses may be an effective therapeutic strategy to prevent and control aGVHD.