Fat-to-blood recirculation of partially dysfunctional PD-1+CD4 Tconv cells is associated with dysglycemia in human obesity

Obesity is characterized by accumulation of T cells in insulin-sensitive tissues, including the visceral adipose tissue (VAT), that can interfere with the insulin signaling pathway eventually leading to insulin resistance (IR) and type 2 diabetes. Here, we found that PD-1+CD4 conventional T (Tconv) cells, endowed with a transcriptomic and functional profile of partially dysfunctional cells, are diminished in VAT of obese patients with dysglycemia (OB-Dys). These cells showed enhanced capacity to recirculate into the bloodstream and had a non-restricted TCRβ repertoire divergent from that of normoglycemic obese and lean individuals. PD-1+CD4 Tconv were reduced in the circulation of OB-Dys, exhibited an altered migration potential, and were detected in the liver of patients with non-alcoholic steatohepatitis. The findings suggest that dysglycemia in individuals with obesity is associated with recirculation of a heterogeneous population of partially dysfunctional PD-1+CD4 Tconv cells. These changes may contribute to the inter-organ crosstalk underlying IR In order to investigate the role of PD-1+ CD4 Tconv cells in the development of dysglycemia in obesity we FACS-sorted PD-1+ CD4 Tconv cells from visceral adipose tissue and peripheral blood of obese patients with and without dysglycemia. RNA extraction was performed from bulk PD-1+ CD4 Tconv cells to perform RNAseq and carry out gene expression analysis. Gene expression profile of PD-1+ CD4 Tconv cells from dysglycemic patients (OB-Dys) was compared with the one from non-diabetic normoglycemic patients (OB-ND).