Rapid adipose tissue expansion triggers proliferation of memory adipose tissue T cells and accumulation of novel T helper 2 (Th2) regulatory cells

Obesity generates a pro-inflammatory state contributing to immune dysregulation and metabolic disease. In response to overnutrition, adipose tissue immune cells undergo dynamic changes featuring a shift from a type 2 anti-inflammatory phenotype in lean adipose tissue to a pro-inflammatory phenotype in obese adipose tissue, contributing to obesity associated adipose tissue inflammation featuring an accumulation of macrophages and T cells. Adipose tissue T cells (ATTs) from mice and humans with obesity have an exhausted phenotype, suggesting chronic activation. However, the mechanism(s) that regulate the balance between anti-inflammatory and pro-inflammatory ATT phenotypes with obesity are not understood. We sought to investigate how and if ATT cells respond to early obesity. We characterized the temporal and phenotypic changes in ATTs in response to initial adipose tissue remodeling, using short-term high fat diet (stHFD) as a model. We observed the accumulation of ATTs in the visceral adipose tissue (VAT) due to the induction of proliferation in memory, and not naïve, ATTs with 7 days of HFD. Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) demonstrated a decrease in Tregs and γδ T cells with an increase in a novel Th2 cell population with immune regulatory capacities featuring expression of the immunoregulatory cytokine Tgfb1, and an activated gene expression profile featuring an increase in Nr4a1 and Itk , in VAT with 14 days of HFD. This study represents the first description of a Th2 regulatory cell population in adipose tissue, and its increase with short-term HFD suggests underexplored mechanisms of ATT subpopulation activation and regulation.