BCL6 inhibits CD4+Foxp3+ regulatory T cell trans‐differentiation into macrophage‐like cells via modulation of chromatin long‐range interactions

Abstract

The mechanisms underlying macrophage (Mϕ) heterogeneity and regulatory T cell (Treg) plasticity remain poorly determined. Here, we determined the mRNA expressions of 208 macrophage subset markers, Mϕ transcription factors (TFs) and other regulators in microarray data. We made the following findings: 1) Tissue Mϕ from lung, liver, spleen and intestine (LLSI) express higher M1 markers than adipose tissues (AT); the markers of Mϕ subsets such as MHb, Mhem, and HA‐Mac are AT‐enriched; and the markers of Mox are bone marrow (BM)‐specific; 2) Proadipogenic TFs C/EBPα, PPARγ and proinflamamtory adipokine leptin upregulate M1 markers; 3) Tissue Mϕ from LLSI and BM express higher levels of T cell co‐inhibition receptor CD274 than that of AT, have higher levels of glycolysis, fatty acid pathway, and fatty acid β‐oxidation pathway than that of AT, and prefer using RAB27A, STX3 to RAB31 and YKT6 in mediating exosome biogenesis and docking; 4) The expressions of 31 markers from 10 Mϕ subsets are modulated in eight groups of total 34 diseases; and a wide spectrum of pathological Mϕ pathways are identified from high hierarchical shared pathways to disease‐specific ones; 5) BCL6 inhibits Treg trans‐differentiation into Mϕ‐like cells; 6) BCL6 expression in Treg determines the status of BCL6 high stable Treg and BCL6 low plastic Treg potentially by exosomes generated from tumor cells and other cell types, respectively; and 7) BCL6 deficiency in Treg upregulates Mϕ TFs via increasing the ratio of upstream chromatin long‐range interaction sites (CLRISs) over downstream CLRISs. Our finding identified pathways underlying Mϕ heterogeneity in pathophysiological conditions and Treg plasticity, which serves as novel therapeutic targets for cancers and inflammation.Support or Funding InformationThis work was supported by NIH grant to Drs. XF. Yang, H. Wang.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.