UC San Diego

Elevated expression of microRNA-23~27~24 (miR-23) family in T cells has been shown to be crucial to restrict follicular helper T (TFH) cell response. Interestingly, like Bcl-6 and many other molecules that play important roles in both TFH cells and germinal center (GC) B cells, two key components in orchestrating proper humoral immunity, we have found that the miR-23 family is also upregulated in germinal center (GC) B cells. Nevertheless, the cell intrinsic role of this miRNA family in regulating GC B cell response has yet to be characterized. In this study, through employing cell type specific gain-of-function and lost-of function approaches, we show the miR-23 family plays an equally important role in regulating GC B cell responses. However, while the entire miR-23 clusters coordinately limit GC B cell responses, individual members of the miR-23 family contribute to GC B cell regulation in distinct manners. Moreover, despite the fact that GC B cell responses were clearly impacted by the deletion or overexpression of the miR-23 family in B cells, the frequencies of TFH cells in those mice remained unchanged. These results implied that while the miR-23 family serves as negative regulators in limiting GC B cell differentiation and function, they might also play a positive role in promoting GC B/TFH cell interaction. Consistent with this notion, our RNA-seq analysis revealed a network of genes involved in GC B cell biology that are respectively up- and down-regulated in the absence of miR-23 family-mediated regulation. Collectively, our work demonstrates that the miR-23 clusters are pivotal molecular regulators to ensure proper GC B cell responses not only through targeting TFH cells as shown previously but also by directly inhibiting GC B cells in a cell-intrinsic manner.