B Cells Suppress IL-2, IFN-γ and TNF-α Production from Alloaggressive CD8⁺ T Cells in a Mismatched Murine Model of Bone Marrow Transplant.

B cells have been variously shown to induce direct tolerance of antigen specific CD8⁺ T cells in models of autoimmunity and tumor immunology. We have previously shown that resting B cells also inhibit anti-tumor T cell function and suppress graft versus host disease (GVHD) in a mismatched mouse model. We have extended these findings to reveal that B cell depletion of the donor graft results in more rapid T cell engraftment and higher IL-2, IFN-γ and TNF-α production by engrafting alloagressive T cells. In turn the degree of cytokine production was highly correlated with the degree of weight loss in mice developing GVHD underscoring the importance of T cell derived inflammatory cytokines in the development of GVHD. Conversely, those mice treated with additional resting B cells at the time of marrow infusion showed lower levels of cytokine production from engrafting T cells and subsequently less GVHD. Further, the amount of INF-γ and TNF-α production from alloaggressive T cells post transplant was substantially greater when a donor splenocytes we used to supplement bone marrow. The clinical score and histological examination of mice undergoing splenocyte + bone marrow transplant showed substantially differences compared to that observed in the bone marrow only model The post splenocyte transplant model reflected a hyperacute GVHD syndrome as opposed to clinically relevant, histologically proven acute GVHD derived from the transplant of bone marrow and furhet indicate that rapid disregulated T cells engraftmnet of central to the onset of devastaing GVHD. These findings indicate that resting B cells may regulate T cell engraftment and activation through regulating T cell homeostasis and suppression of inflammatory cytokines. B cells therefore may potentially be used therapeutically to limit GVHD mediated by alloaggressive T cells, whilst profound pre-transplant depletion of B cells may be detrimental to transplant outcome due to the promotion of GVHD.