Accumulation of γδ T cells in visceral fat with aging promotes chronic inflammation

Abstract

Adipose tissue dysfunction is strongly linked to the development of chronic inflammation and cardiometabolic disorders in aging. While much attention has been given to the role of resident adipose tissue immune cells in the disruption of homeostasis in obesity, age-specific effects remain understudied. Here, we identified and characterized a population of γδ T cells, which show unique age-dependent accumulation in the visceral adipose tissue (VAT) of both mice and humans. Diet-induced obesity likewise increased γδ T cell numbers; however, the effect was greater in the aged where the increase was independent of fat mass. γδ T cells in VAT express a tissue-resident memory T cell phenotype (CD44hiCD62LlowCD69+) and are predominantly IL-17A-producing cells. Transcriptome analyses of immunomagnetically purified γδ T cells identified significant age-associated differences in expression of genes related to inflammation, immune cell composition, and adipocyte differentiation, suggesting age-dependent qualitative changes in addition to the quantitative increase. Genetic deficiency of γδ T cells in old age improved the metabolic phenotype, characterized by increased respiratory exchange ratio, and lowered levels of IL-6 both systemically and locally in VAT. Decreased IL-6 was predominantly due to reduced production by non-immune stromal cells, primarily preadipocytes, and adipose-derived stem cells. Collectively, these findings suggest that an age-dependent increase of tissue-resident γδ T cells in VAT contributes to local and systemic chronic inflammation and metabolic dysfunction in aging.

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A single-cell atlas of the aging murine ovary

“…However, whether these cells are protective or deleterious in fibrosis appears to be tissue- and context-dependent 88,89 . For instance, age-related accumulation of Type 17 γδTs contributes to chronic inflammation in adipose tissue 90 . In the ovary, expansion of the Type 17 γδTs could either promote fibrosis or be a compensatory attempt to dampen the fibrotic environment.…”

Mechanisms of γδ T cell accumulation in visceral adipose tissue with aging

“…This increase occurs independent of adiposity and without regard for sex. In the absence of γδ T cells (TCRδ KO mice), inflammation, both locally in VAT and systemically, is reduced in aged mice confirming a role for these cells in age-associated inflammation ( Bruno et al, 2022 ). Deficiency of γδ T cells in old age also improved the metabolic phenotype characterized by increased respiratory exchange ratio.…”

“…We recently reported that γδ T cells are increased by aging in VAT of mice and humans ( Bruno et al, 2022 ). This increase occurs independent of adiposity and without regard for sex.…”