IL-4-producing B cells regulate T helper cell dichotomy in type 1-and type 2-controlled diseases

Interleukin-4 (IL-4)-induced T helper (Th) 2 cells promote susceptibility to the protozoan parasite Leishmania major, while conferring immunity to the intestinal trematode Schistosoma mansoni. Here, we report that abrogation of IL-4 receptor alpha (IL-4R alpha) signaling on B cells in BALB/c mice (mb1(cre)IL-4R alpha(-/lox)) transformed nonhealer BALB/c to a healer phenotype with an early type 1 and dramatically reduced type 2 immune response and an absence of ulceration and necrosis during cutaneous leishmaniasis. From adoptive reconstitution and mixed bone-marrow chimera studies in B cell-deficient (mu MT) mice, we reveal a central role for B cell-derived IL-4 and IL-4R alpha in the optimal induction of the susceptible type 2 phenotype to L. major infection. We further demonstrate that the absence of IL-4R alpha signaling on B cells exacerbated S. mansoniinduced mortality and pathology in BALB/c mice, due to a diminished type 2 immune response. In both disease models, IL-4-R alpha-responsive B cells displayed increased IL-4 production as early as day 1 after infection. Together, these results demonstrate that IL-4-producing and IL-4R alpha-responsive B cells are critical in regulating and assisting early T helper dichotomy toward Th2 responses, which are detrimental in cutaneous leishmaniasis but beneficial in acute schistosomiasis.