B cell-intrinsic and lymphocyte extrinsic miR-21 drive optimal germinal center and antibody responses

Abstract

Abstract Germinal centers (GCs) generate high affinity B cell responses that are protective against infection but can produce autoreactive responses when dysregulated. MicroRNAs (miRNAs) have been implicated in the regulation of GC fate, though the role of many individual miRNAs remains uncharacterized. Here, we demonstrate that within the GC, miR-21 promotes T follicular helper cell (Tfh), T follicular regulatory cell (Tfr), and GC B cell responses, as well as downstream antibody production. Regulation of the GC response by miR-21 requires multiple mechanisms, occurring in both B cells and innate cells. B cell-intrinsic miR-21 drives GC B cell expansion by promoting B cell activation and proliferation. MiR-21 target gene expression arrays have revealed several putative target genes in B cells, suggesting that miR-21 targets negative regulators of proliferative pathways to enhance B cell proliferation and GC responses. In contrast, Tfh and Tfr are driven by miR-21 in a B and T cell extrinsic manner, likely by innate cells. Our data suggest that miR-21 modifies the cytokine microenvironment, which impacts regulatory T cell expansion and Tfh programs. Therefore, the synergy of B cell intrinsic and lymphocyte extrinsic miR-21 activity is required to generate optimal GC and Ab responses. Of clinical relevance, we also found that upregulation of miR-21 in autoimmune-prone mice drives autoantibody responses, implicating miR-21 in both anti-pathogen responses and its dysregulation in autoimmunity. Therefore, dampening miR-21 function may provide a strategy for autoimmune therapeutics. Alternatively, boosting miR-21 activity in healthy individuals could allow more efficient generation of protective antibody following vaccination.