miR-146a restricts germinal center B cell responses through targeting CD40 signaling pathway

Abstract The germinal center (GC) reaction is the hallmark of B cell-mediated immune responses to T cell-dependent (TD) antigens. Engagement of CD40 by its ligand, CD154, which is expressed on activated CD4+ T cells, follicular helper T (Tfh) cells in particular, is crucial for TD humoral immunity. Previously, it has been demonstrated that miR-146a serves as a molecular break in limiting Tfh cells and the resultant GC B cell responses. Here, by taking the mixed bone marrow chimeras as well as the cell-type-specific miR-146a deletion approaches, we show that like Tfh cells, elevated levels of miR-146a in B cells are equally important in controlling humoral immunity as miR-146a deficiency leads to increased GC B cell differentiation. Moreover, deletion of miR-146a specifically in isotype-switched B cells also resulted in augmented GC responses, suggesting that continued miR-146a expression in GC B cells is required for the maintenance of optimal GC reactions. Mechanistically, we found that miR-146a-ablated B cells exhibit elevated CD40 expression and that enhanced CD40 signaling is accounted for the dysregulated GC responses in mice with B cell-specific miR-146a ablation. Together, our study demonstrates an indispensable role of miR-146a in restricting GC B cell responses and suggests that miR-146a is a critical negative regulator in controlling both T and B cells, two key arms in orchestrating protective humoral immunity.