Using Ezh2-deficient iNKT cells, Dobenecker et al. show that loss of H3K27me3 at the bivalently marked PLZF promoter is an essential link between TCR specificity and iNKT development in mice.

PRC2 is a known chromatin regulator. Here the authors show novel cytosolic components of PRC2 and that PRC2 inactivation results in attenuation of MAPK/Erk signaling and impaired T cell activation. Systemic PRC2 inhibition in vivo cures the autoimmune syndrome caused by regulatory T cell depletion.

Edited by Wilfried Ellmeier Humoral immunity in mammals relies on the function of two developmentally and functionally distinct B-cell subsets-B1 and B2 cells. While B2 cells are responsible for the adaptive response to environmental antigens, B1 cells regulate the production of polyreactive and low-affinity antibodies for innate humoral immunity. The molecular mechanism of B-cell specification into different subsets is understudied. In this study, we identified lysine methyltransferase NSD2 (MMSET/WHSC1) as a critical regulator of B1 cell development. In contrast to its minor impact on B2 cells, deletion of the catalytic domain of NSD2 in primary B cells impairs the generation of B1 lineage. Thus, NSD2, a histone H3 K36 dimethylase, is the first-in-class epigenetic regulator of a B-cell lineage in mice.

Humoral immunity in mice and man relies on the function of two developmentally and functionally distinct B cell subsets -B1 and B2 cells. While B2 cells are responsible for most of the adaptive response to environmental antigens, B1 cells, which are comprised of phenotypically distinct B1a and B1b cells, are carriers of the innate humoral immunity that relies on production of poly-reactive and low affinity antibodies. The molecular mechanism of B cell specification into different subsets is not well established. Here we identified lysine methyltransferase MMSET/NSD2 as a critical regulator of the B1 cell population. We show that NSD2 deficiency in B cell precursors prevents generation of the B1 cell compartment, while having a minor impact on B2 cells. Our data revealed MMSET/NSD2, which catalyzes histone H3 lysine 36 di-methylation, as the first in class epigenetic master regulator of a major B cell lineage in mice.