Il-4-Responsive B Cells Are Detrimental During Chronic Tuberculosis Infection In Mice

In tuberculosis, T cell-mediated immunity is extensively studied whilst B cells received limited attention in human and mice. Of interest, Mycobacterium tuberculosis (Mtb) does increase IL-4 Receptor-alpha (IL4R alpha) expression in murine B cells. To better understand the role of IL4R alpha signalling in B cells, we compared wild type mice with B cell-specific IL4R alpha deficient mice (mb1(cre)IL-4R alpha(-/lox) mice). Chronic Mtb aerosol infection in mb1(cre)IL-4R alpha(-/lox) mice reduced lung and spleen bacterial burdens, compared to littermate (IL-4R alpha(-/lox)) control animals. Consequently, lung pathology, inflammation and inducible nitric oxide synthase (iNOS) expression were reduced in the lungs of mb1(cre)IL-4R alpha(-/lox) mice, which was also accompanied by increased lung IgA and decreased IgG1 levels. Furthermore, intratracheal adoptive transfer of wild-type B cells into B cell-specific IL4R alpha deficient mice reversed the protective phenotype. Moreover, constitutively mCherry expressing Mtb showed decreased association with B cells from mb1(cre)IL-4R alpha(-/lox) mice ex vivo. In addition, supernatants from Mtb-exposed B cells of mb1(cre)IL-4R alpha(-/lox) mice also increased the ability of macrophages to produce nitric oxide, IL-1 beta, IL-6 and TNF. Together, this demonstrates that IL-4-responsive B cells are detrimental during the chronic phase of tuberculosis in mice with perturbed antibody profiles, inflammatory cytokines and tnf and stat1 levels in the lungs.