Marginal zone B cells induce T cell homeostatic proliferation following antibody-mediated lymphoablation

Abstract

Abstract Antibody-mediated lymphoablation is commonly used in clinical transplantation. Using mouse model of heart transplantation and murine anti-thymocyte globulin (mATG) lymphoablation, we previously showed that B cell-derived IL-1β and IL-6 are critical mediators of homeostatic T cell proliferation. While marginal zone (MZ) B cells are best known as important sensors and amplifiers of inflammation, their role in depletion-induced lymphopenia has not been previously addressed. The goal of this study was to test the contribution of distinct B cell subsets to proinflammatory cytokine production and T cell homeostatic reconstitution. B6 (H-2b) recipients of BALB/c (H-2d) heart allografts were treated with mATG (d. 0, 4). At d. 8 posttransplant, the proportion of IL-1β, IL-6 and TNF-α secreting cells was significantly higher within MZ vs follicular (FO) B cell subset. Depletion of both FO and MZ B cells with anti-CD20 mAb in addition to mATG (d. -3, 11) significantly diminished T cell reconstitution and prolonged heart allograft survival compared to mATG treatment alone. Notably, specific MZ B cell depletion with anti-VLA4 and anti-LFA1α mAbs (d. -4, -2) resulted in similarly impaired T cells recovery along with improved heart allograft survival. Consistent with these findings, mATG treated Notch2flox/flox CD19Cre/+ mice, which lack MZ B cells but contain normal numbers of FO B cells, had delayed T cell recovery and prolonged heart allograft survival compared to WT recipients. These results show the critical role of MZ B cells in stimulating homeostatic T cell proliferation in lymphopenic heart allograft recipients and suggest that transient removal of MZ B cells may improve the efficacy of lymphoablative induction therapies.