A germinal center B cell-specific long non-coding RNA regulates the germinal center response

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Abstract Long non-coding RNAs are a unique class of molecules involved in an exceptional variety of cellular processes, including transcriptional, translational, and epigenetic regulation. Here, we report the initial characterization of a lncRNA expressed specifically in the germinal center--organized sites of B cell proliferation, somatic hyper-mutation, and cellular differentiation that develop in response to antigenic challenge. The precise signals dictating how and when differentiated cells, such as memory B cells and long-lived plasma cells, exit the GC reaction remain incompletely understood. Thus, additional levels of molecular regulation are likely at work in the coordination of these diverse processes. We identify GCLnc1--a novel, nuclear-localized lncRNA--as a regulator of the GC reaction. As GCLnc1 is located adjacent to the murine Bcl6 locus, this lncRNA has the potential to modulate expression of key transcription factors controlling B cell identity and/or differentiation. Interestingly, forced over-expression of GCLnc1 in B cells led to upregulation of TFs associated with plasma cell identity, such as IRF4 and Blimp-1. When adoptively transferred in vivo, over-expression of GCLnc1 led to transduced B cells predominantly adopting a non-GC phenotype at the typical peak GC response, in addition to enhancing expression of IRF4 and Blimp-1. Genetic deletion of GCLnc1 led to reduced frequency of GC B cells, decreased Bcl6 expression, and dysregulated light zone/dark zone distribution in response to NP-KLH immunization. Collectively, we suggest GCLnc1 plays a key role in the integration of signaling events during the GC reaction, and may modulate the processes that drive GC exit.