THE ROLE OF EZH2 IN B CELL DEVELOPMENT AND ADAPTIVE IMMUNITY

Polycomb group (PcG) proteins are epigenetic modifiers that act as transcriptional repressors modulating chromatin accessibility of target genes. Methylation on lysine-27 of histone H3 (H3K27me3) catalyzed by the PcG protein Ezh2 is a bona fide epigenetic mark linked to lineage specification and identity. Analyses on PcG mutant mice have revealed an essential role of PcG proteins in haematopoiesis. In the B cell compartment, Ezh2 is expressed in progenitor B cells and is strongly induced upon recruitment of naïve B cells into the germinal center (GC) reaction, during a T cell dependent immune response. Using a conditional gene targeting approach in vivo, we addressed the effects of Ezh2 inactivation on GC B cell responses, terminal differentiation, memory B cell generation and function. Conditional inactivation of Ezh2 in GC B cells caused a significant reduction in numbers and frequency of GC B cells. Loss of Ezh2 promoted a significant increase in the fraction of GC B cells undergoing apoptosis. As a result of the impaired GC reaction, serum titers of antigen-specific, class-switched antibodies were significantly decreased and formation of memory B cells significantly impaired in mutant mice. Instead, mutant GC B cells showed premature onset of terminal differentiation, as assessed by the induction of genes coding for the master regulators of plasma cell differentiation Prdm1, Irf4 and Xbp1. In this work we provide evidence that sets the ground for a model where Ezh2 together with GC master regulator Bcl6 supports GC B cell identity and function.