B cell-derived IL-1β and IL-6 drive homeostatic T cell recovery following lymphoablation

Abstract

Abstract T cell reconstitution after lymphoablation in allograft recipients may lead to acute rejection and poor graft outcome. Using a mouse model of heart transplantation and murine anti-thymocyte globulin (mATG) we showed that while T cell recovery depends on B cells, B cell MHC expression is dispensable. The goal of this study was to investigate the role of B cell-derived IL-1β and IL-6 in T cell homeostatic reconstitution after mATG lymphoablation. The NanoString analysis showed that mATG upregulated IL-1β and IL-6 gene expression in recipient B cells. To validate NanoString findings, IL-1β and IL-6 expression was measured by intracellular flow cytometry. Following heart allograft placement and mATG treatment, B cells are the main source of IL-1β and IL-6, and these cytokines mutually regulate each other’s production. Either treatment with anti-IL-1β mAb or the use of IL-1R1 KO, caspase-1 KO and MyD88 KO recipients diminished both CD4+ and CD8+ T cell recovery along with improved heart allograft survival and decreased donor-reactive IFN-γ producing cells after mATG treatment. Similarly, in vivo IL-6 neutralization with mAb or using IL-6 KO recipients delayed CD4+ and CD8+ T cell recovery, markedly prolonged heart allograft survival and decreased donor-specific T cell responses suggesting that IL-1β and IL-6 are essential for optimal T cell recovery. Adoptive B cell transfers into μMT mice showed that B cell-derived IL-1β and IL-6 supported CD8+ T cells recovery. The absence of either IL-1R or IL-6R on CD8+ T cells markedly impaired their homeostatic recovery following mATG depletion. These findings reveal the essential role of B cell-derived IL-1β and IL-6 during homeostatic T cell expansion in a clinically relevant model of lymphoablation.