Devadatta Gosavi

Atherosclerosis destabilizes regulatory T cells (Tregs) resulting in multiple families of exTregs

Distinct Treg subsets in human peripheral blood are defined by unique transcriptomic signatures 2252633

Regulatory CD4+ T cells (Tregs) are critical for maintaining tolerance to self. Chronic inflammation can cause Treg instability which is defined by loss of CD25 and the lineage-defining transcription factor FOXP3, resulting in exTreg cells. To better understand the factors driving Treg to exTreg conversion, we analyzed transcriptomes of Treg subsets expressing varied levels of CD25 and FOXP3 in human peripheral blood CD4+ T cells. We found differential expression of genes related to inflammatory signaling (IFNG, TNF), cytotoxicity (PRF1, GZMB) and cellular stress (HSPA5). This was confirmed at the protein level by flow cytometry. Distinct Treg populations were also defined by unique metabolic profiles suggesting a role of cell-intrinsic metabolic programs in maintaining Treg stability. Our findings start to define novel cellular pathways contributing to Treg homeostasis and instability in human peripheral blood. We acknowledge the support from National Institutes of Health (awards P01 HL136275 and R35 HL145241) to K.L. Lymphocyte Differentiation and Peripheral Maintenance (LYM)