Innate Immune B Cell Activation by Leishmania donovani Exacerbates Disease and Mediates Hypergammaglobulinemia

•Leishmania donovani triggers endosomal TLRs in B cells•Innate B cell activation results in IL-10 and type I IFN induction•IFN-I is involved in a positive regulatory loop enhancing cytokine and TLR expression•Innate B cell activation and IFN-I govern antibody production during disease

SummaryParticipation of B cells in the immune response by various antibody-independent mechanisms has recently been uncovered. B cells producing cytokines have been described for several infections and appear to regulate the adaptive immune response. B cell activation by Leishmania donovani results in disease exacerbation. How Leishmania activates B cells is still unknown. We show that L. donovani amastigotes activate B cells by triggering endosomal TLRs; this activation leads to the induction of various cytokines. Cytokine expression is completely abrogated in B cells from Ifnar−/− mice upon exposure to L. donovani, suggesting an involvement of IFN-I in a positive feedback loop. IFN-I also appears to enhance the expression of endosomal TLRs following exposure to L. donovani. Cell-specific ablation of endosomal TLR signaling in B cells revealed that innate B cell activation by L. donovani is responsible for disease exacerbation through IL-10 and IFN-I production and for the promotion of hypergammaglobulinemia.

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