The transcription factor RORa plays a major role in generation and maintenance of human and mouse memory B cells

Memory B cells (MBCs) are antigen-specific, long-lived and capable of differentiating into plasma cells upon reencounter with antigen to make large amounts of high affinity antibodies. Our previous integrative analysis of human MBC transcriptome and chromatin landscape suggested RORa to be important to the identity of human class-switched (sw)MBCs (Moroney et al., Nat Commun. 11:5435, 2020). Accordingly, we found RORa to be highly expressed in not only human but also mouse swMBCs. Supporting a role of RORa in swMBC generation, Aicda^creRora^fl/fl mice showed, upon immunization with NP₁₆-CGG, reduced high affinity anti-NP antibodies and NP-specific swMBCs, leading to a defective anamnestic response, despite seemingly normal germinal center B cell differentiation, class-switch DNA recombination and plasma cell differentiation. Using tamoxifen-inducible B cell RORa conditional knockout CD19^cre/ERT2Rora^fl/fl mice, RORa ablation in NP₁₆-CGG-induced swMBCs led to loss of anamnestic anti-NP response, highlighting the importance of RORa in generation and maintenance of swMBCs. Integrated RNA-seq and Cut&Tag analyses in human and mouse swMBCs provided comprehensive insights into the role of RORa in epigenetic regulation of such B cell transcriptional programs. Thus, our findings establish RORa as a critical regulator of swMBC generation and maintenance, thereby opening new avenues of investigation in the mechanisms of B cell differentiation and possibly vaccine development.