B cell-derived IL-1ß and IL-6 drive T cell reconstitution following lymphoablation.

Understanding the mechanisms of T cell homeostatic expansion is crucial for clinical applications of lymphoablative therapies. We previously established that T cell recovery in mouse heart allograft recipients treated with anti-thymocyte globulin (mATG) critically depends on B cells and is mediated by B cell-derived soluble factors. B cell production of interleukin (IL)-1ß and IL-6 is markedly upregulated after heart allotransplantation and lymphoablation. Neutralizing IL-1ß or IL-6 with mAb or the use of recipients lacking mature IL-1ß, IL-6, IL-1R, MyD88, or IL-6R impair CD4+ and CD8+ T cell recovery and significantly enhance the graft-prolonging efficacy of lymphoablation. Adoptive co-transfer experiments demonstrate a direct effect of IL-6 but not IL-1ß on T lymphocytes. Furthermore, B cells incapable of IL-1ß or IL-6 production have diminished capacity to mediate T cell reconstitution and initiate heart allograft rejection upon adoptive transfer into mATG treated B cell deficient recipients. These findings reveal the essential role of B cell-derived IL-1ß and IL-6 during homeostatic T cell expansion in a clinically relevant model of lymphoablation.