Visceral fat around the inner organs is a metabolically active tissue, and more of it is entirely detrimental to long-term health. These fat deposits interact with the immune system in a number of distinct ways to produce chronic inflammation, and that inflammation in turn drives the onset and progression of tissue dysfunction and all of the common age-related conditions. For example, visceral fat encourages the accumulation of senescent cells and their pro-inflammatory signaling, while visceral fat cells signal in ways that mimic infection, as well as producing DNA debris that activates the innate immune system. Given the number of known inflammatory processes, we might expect researchers to uncover further, novel mechanisms involved in generating inflammation in visceral fat, as is the case here.
γδ T cells are a unique and poorly understood class of lymphocytes generally regarded for their role in barrier protection with functionally distinct subpopulations residing in epithelial tissues, including those of the skin, gut, and lung. In addition to responding to antigen presentation via the T cell receptor, similar to conventional T cells (regulatory, helper, and cytotoxic T cells) of the adaptive immune system, γδ T cells can respond directly to cytokines and other intact proteins without antigen processing and presentation, and have the capacity to phagocytize much like innate immune cells.
In adipose tissues, contrary to their traditional function in infection control, γδ T cells appear to play major roles in maintaining homeostasis with respect to inflammation and insulin sensitivity. Adipose tissue γδ T cells have been shown to increase in number in mouse models of diet-induced obesity, where they promote macrophage accumulation, inflammation, and insulin resistance. More recently, they were reported to regulate adipose tissue regulatory T cell homeostasis and thermogenesis in adolescent and young-adult mice.
Here, we identified and characterized a population of γδ T cells, which show unique age-dependent accumulation in the visceral adipose tissue 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. 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 visceral adipose tissue. 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 visceral adipose tissue contributes to local and systemic chronic inflammation and metabolic dysfunction in aging.