Single cell sequencing of the effects of blocking lymphotoxin alpha in the mesenteric lymph node and spleen

TNFDARE+/- mice develop TNF-driven transmural ileitis and mesenteric inflammation, and lose body mass, reminiscent of human Crohn’s disease. Here, we report that B cells regulate body mass and intestinal permeability during ileitis in a manner that is linked to lymphotoxin (LT)-a but not LTb, whereas B cell LTab2 promoted mesenteric TLS that suppressed lymphatic outflow. Using genetic approaches and neutralizing reagents, we connect LTa3, a ligand for TNFRs, expressed by activated follicular B cells to their appearance in draining lymph nodes and the generation or persistence of IgA+ ileal plasma cells. Some of the same B cells also expressed TNF. Opposite to LTa, expression of TNF by B cells was disadvantageous to the development of IgA+ ileal plasma cells, suggesting counterbalancing interplay between LTa3 and TNF in ileitis. These data highlight a multi-faceted role of B cells in ileitis that includes an unexpected role for B cell-derived LTa3 in the maintenance of body weight.