MiR-146a as a negative regulator in controlling humoral immunity (IRM10P.612)

Abstract

Abstract The germinal center (GC) reaction is the hallmark of B cell-mediated immune responses to T cell-dependent antigens Recently, a specialized immune population of follicular helper T (Tfh) cells has emerged as a central player in driving GC B cell response and promoting humoral immunity. It has been shown that many genes that are critically involved in the generation of GC B cells also play an indispensable role in the differentiation of Tfh cell population from naive T cells. Here, we show miR-146a is highly upregulated in both Tfh and GC B cells. Our analysis of mixed bone marrow chimeras as well as mice with cell-type-specific deletion of miR-146a demonstrated that elevated levels of miR-146a in both Tfh and B cells are pivotal to control corresponding responses during GC reactions in a cell intrinsic manner. Moreover, deletion of both miR-146a and its paralog, miR-146b resulted in further enhance phenotypes, suggesting that both miR-146 family members contribute to the negative regulation of humoral immunity. Finally, combining transcriptional profiling and biochemical approaches including HITS-CLIP (high-throughput sequencing of RNAs isolated by crosslinking immunoprecipitation), several miR-146a targets with potential roles in controlling Tfh and GC B cell responses have been identified. In sum, our study identifies a miRNA family highly enriched in GC cell subsets with the capacity to control GC reaction by limiting differentiation of Tfh and GC B cells.