Augmented CD47 expression impairs alloreactive T-cell clearance after allo-HCT.

Abstract

Graft-versus-Host disease (GvHD) ensues as the most common non-relapse complication after allogeneic hematopoietic cell transplantation (allo-HCT). A pivotal goal in GvHD management revolves around quelling inflammation. Phagocytic clearance of inflammatory cells contributes substantially to termination of inflammatory processes. Nevertheless, the precise functions of phagocytosis in GvHD remain largely unclear. In this study, we identified the "don't eat me"-signal CD47 as a promising target for therapeutic interventions aimed at eradicating alloreactive T-cells subsequent to allo-HCT. Analysis of global data sets revealed a remarkable upregulation of CD47 expression on T-cells residing in the ileum of patients with inflamed intestine. Building on this finding, we examined CD47 levels in the gastrointestinal tract (GIT) following allo-HCT. Our work not only confirmed upregulated CD47 expression in the GIT of GvHD patients, but also identified CD47 on T-cells in the ileum of GvHD mice after allo-HCT. Additionally, we found that activated donor T-cells suppress antibody-dependent cellular phagocytosis (ADCP) via CD47 signaling in vitro. Application of anti-CD47 antibodies significantly invigorated the impaired ADCP of activated T-cells. Administering anti-CD47 antibodies to mice elevated phagocytosis of T-cells in the GIT, induced immunosuppressive responses and improved survival. Finally, transplantation of CD47 deficient donor T-cells significantly improved clinical GvHD score with improved survival after allo-HCT. Collectively, our findings illuminate CD47 upregulation as pivotal mechanism in GvHD patients, leading to impaired phagocytic clearance of alloreactive T-cells. This study proposes that anti-CD47 treatment could rectify the compromised phagocytosis of alloreactive T-cells, thereby aiding in the resolution of inflammation after allo-HCT.