The Tetraspanin Protein CD37 Regulates IgA Responses and Anti-Fungal Immunity

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Abstract
Immunoglobulin A (IgA) secretion by plasma cells in the immune system is critical for protecting the host from environmental and microbial infections. However, the molecular mechanisms underlying the generation of IgA+ plasma cells remain poorly understood. Here, we report that the B cell–expressed tetraspanin CD37 inhibits IgA immune responses in vivo. CD37-deficient (CD37−/−) mice exhibit a 15-fold increased level of IgA in serum and significantly elevated numbers of IgA+ plasma cells in spleen, mucosal-associated lymphoid tissue, as well as bone marrow. Analyses of bone marrow chimeric mice revealed that CD37–deficiency on B cells was directly responsible for the increased IgA production. We identified high local interleukin-6 (IL-6) production in germinal centers of CD37−/− mice after immunization. Notably, neutralizing IL-6 in vivo reversed the increased IgA response in CD37−/− mice. To demonstrate the importance of CD37—which can associate with the pattern-recognition receptor dectin-1—in immunity to infection, CD37−/− mice were exposed to Candida albicans. We report that CD37−/− mice are evidently better protected from infection than wild-type (WT) mice, which was accompanied by increased IL-6 levels and C. albicans–specific IgA antibodies. Importantly, adoptive transfer of CD37−/− serum mediated protection in WT mice and the underlying mechanism involved direct neutralization of fungal cells by IgA. Taken together, tetraspanin protein CD37 inhibits IgA responses and regulates the anti-fungal immune response. Antibody, or immunoglobulin (Ig), production by plasma cells in the immune system is important for protecting the host from microbial infections. IgA is the most abundant antibody isotype produced in the body. However, the molecular mechanisms underlying the generation of IgA–producing plasma cells remain poorly understood. We now report that the B cell–expressed protein CD37 regulates IgA immune responses, both in steady-state conditions and during infection. We found highly increased levels of IgA in serum and elevated numbers of IgA+ plasma cells in lymphoid tissue of mice that are deficient for CD37 (CD37−/− mice). To demonstrate the importance of CD37 in immunity to infection, CD37−/− mice were exposed to the fungus Candida albicans. C. albicans can cause systemic infection with high mortality in immunocompromised patients. We demonstrate that CD37−/− mice are evidently better protected from infection than wild-type mice, which was dependent on C. albicans–specific IgA antibodies. The underlying mechanism involved direct neutralization of fungal cells by IgA. In summary, the B cell protein CD37 inhibits IgA responses and anti-fungal immunity. This study may contribute to the development of novel immunotherapeutic approaches for invasive fungal disease.

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