Differential regulation of B cell responses to acute and chronic infection by histone-modifying complexes

Abstract

Abstract Molecular regulation of B cell differentiation is critical for formation of immune memory and becomes dysregulated in B cell lymphomas. Alterations in the genomic landscape that allow or restrict access of transcription factors are critical to enact gene expression profiles that in turn drive cell differentiation. Chromatin accessibility can be modulated by enzymes that modify the N-terminal tail of histones. The Trithorax group protein MLL1 forms histone-modifying complexes to permit transcription, whereas the two Polycomb repressor complexes (PRC) work together to repress gene expression. The dynamic regulation of these complexes can modulate B cell fate and function during immune responses. Yet, little is known about the temporal and spatial requirements of MLL1, canonical PRC1 and PRC2 during acute and chronic immune responses. Deletion of the PRC2 member EED (Eedf/fCd23Cre/+ mice) resulted in a complete absence of GC and B cell memory following immunization or influenza infection. Mll1f/fCd23Cre/+ mice also could not mount an effective GC response to immunization, yet their plasmablast response remained intact. In contrast, the canonical PRC1 member BMI-1 was required for plasmablast but not GC responses. Surprisingly, the requirement for EED and MLL1 in a chronic persisting infection differed from acute responses. In contrast to acute responses, Eedf/fCd23Cre/+ mice infected with LCMV-Docile or P. chabaudi had normal GC formation, whereas Mll1f/fCd23Cre/+ mice formed GCs to the acute LCMV strain but not in chronic infection. Together, our data demonstrate the differential requirements of these complexes in B cell fate decisions, as well as suggest epigenetic regulatory checks are subverted in persisting infections.