IL-1β And IL-6 Facilitate T Cell Reconstitution In Heart Allograft Recipients Treated With Anti-Thymocyte Globulin

Abstract

Abstract Antibody-mediated lymphocyte depletion is used in solid organ transplantation. T cell reconstitution after lymphoablation may lead to acute rejection and poor graft outcome. We investigated the mechanisms of T cell reconstitution in heart allograft recipients treated with murine anti-thymocyte globulin (mATG). B cell depletion with anti-mouse CD20 mAb significantly diminished T cell reconstitution in B6 (H-2b) recipients of BALB/c (H-2d) heart allografts treated with mATG. However, cognate T/B cell interactions were dispensable for T cell recovery suggesting the potential role of B cell derived cytokines. The NanoString gene expression analysis of isolated B cells showed that mATG upregulated IL-1β and IL-6 expression in CD4 T cell-dependent manner. Intracellular flow cytometry confirmed that B cells are the major source of IL-1β and IL-6 following mATG treatment. The proportion of IL-1β secreting B cells was increased in mATG treated compared to untreated recipients, whereas IL-6 producing B cells were not significantly affected by lymphoablation. Neutralization of either IL-1β or IL-6 with mAb significantly decreased T cell recovery and extended heart allograft survival in mATG treated recipients. To further test the role of B cell derived IL-1β, we injected either WT or Caspase-1−/− B cells into B cell deficient μMT mice followed by BALB/C heart transplantation and mATG treatment. Caspase-1 deficiency in injected B cells resulted in significantly lower CD8 T cell recovery. Our results show the novel functions of IL-1β and IL-6 in regulating homeostatic T cell recovery following mATG treatment. IL-1β and IL-6 neutralization may be a promising strategy for enhancing the efficacy of mATG lymphoablation in transplant recipients.