Follicular helper T (TFH) cells and follicular regulatory T (TFR) cells regulate the quantity and quality of humoral immunity. Although both cell types highly express the co-stimulatory receptor ICOS and require the transcription factor Bcl-6 for their differentiation, the ICOS-dependent pathways that coordinate their responses are not well understood. Here we report that ICOS activation in CD4+ T cells promotes the interaction of the p85α regulatory subunit of the signaling kinase PI3K and intracellular osteopontin (OPN-i), followed by nuclear translocation of OPN-i, interaction with Bcl-6 and protection of Bcl-6 from ubiquitin-dependent proteasome degradation. Post-translational protection of Bcl-6 expression by OPN-i is essential for sustained TFH and TFR cell responses and regulation of the germinal center B cell response to antigen. As such, the p85α–OPN-i axis represents a molecular bridge that couples ICOS activation to Bcl-6-dependent functional differentiation of TFH and TFR cells and suggests new therapeutic avenues to manipulate their responses.

Changes of histone modification status at critical lineage-specifying gene loci in multipotent precursors can influence cell fate commitment. The contribution of these epigenetic mechanisms to natural killer (NK) cell lineage determination from common lymphoid precursors is not understood. Here we investigate the impact of histone methylation repressive marks (H3 Lys27 trimethylation; H3K27 me3 ) on early NK cell differentiation. We demonstrate that selective loss of the histone-lysine N-methyltransferase Ezh2 (enhancer of zeste homolog 2) or inhibition of its enzymatic activity with small molecules unexpectedly increased generation of the IL-15 receptor (IL-15R) CD122 + NK precursors and mature NK progeny from both mouse and human hematopoietic stem and progenitor cells. Mechanistic studies revealed that enhanced NK cell expansion and cytotoxicity against tumor cells were associated with up-regulation of CD122 and the C-type lectin receptor NKG2D. Moreover, NKG2D deficiency diminished the positive effects of Ezh2 inhibitors on NK cell commitment. Identification of the contribution of Ezh2 to NK lineage specification and function reveals an epigenetic-based mechanism that regulates NK cell development and provides insight into the clinical application of Ezh2 inhibitors in NK-based cancer immunotherapies.epigenetic regulation | NKG2D | hematopoietic stem and progenitor cells | histone modification | innate immunity

Macrophages are major cell types of the immune system, and they comprise both tissue-resident populations and circulating monocyte-derived subsets. Here, we discuss microglia, the resident macrophage within the central nervous system (CNS), and CNS-infiltrating macrophages. Under steady state, microglia play important roles in the regulation of CNS homeostasis through the removal of damaged or unnecessary neurons and synapses. In the face of inflammatory or pathological insults, microglia and CNS-infiltrating macrophages not only constitute the first line of defense against pathogens by regulating components of innate immunity, but they also regulate the adaptive arms of immune responses. Dysregulation of these responses contributes to many CNS disorders. In this overview, we summarize the current knowledge regarding the highly diverse and complex function of microglia and macrophages during CNS autoimmunity—multiple sclerosis and cancer—malignant glioma. We emphasize how the crosstalk between natural killer (NK) cells or glioma cells or glioma stem cells and CNS macrophages impacts on the pathological processes. Given the essential role of CNS microglia and macrophages in the regulation of all types of CNS disorders, agents targeting these subsets are currently applied in preclinical and clinical trials. We believe that a better understanding of the biology of these macrophage subsets offers new exciting paths for therapeutic intervention.