The Role of Adipose Tissue-Resident Gamma Delta T Cells in Age-Associated Inflammation and Metabolic Dysfunction: AFAR New Investigator Award

Abstract Detailed description of model system used for the proposed research: C57BL/6 mice, transgenic mouse strains (TCRδ and IL-17A KO), primary mouse cells, cell lines (human and mouse) Adipose tissue dysfunction is linked to metabolic derangements and chronic low-grade systemic inflammation, which are characteristic of the aging process and underlie numerous age-related pathologies. This proposal is centered on our novel findings that visceral adipose tissue (VAT) of aged mice contains nearly 10-fold more gamma delta (γδ) T cells than young-adult mice and that aged mice lacking γδ T cells have reduced systemic and VAT inflammation, and an improved metabolic phenotype. Our central hypothesis is that accumulation of γδ T cells in VAT promotes age-associated adipose tissue dysfunction. The manner with which these cells come to accumulate in VAT with age, and the mechanisms for their action specifically in VAT are not known. Specific Aim 1 will characterize the VAT γδ T cell pool and delineate age-dependent differences. Specific Aim 2 will establish that γδ T cells are drivers of preadipocyte senescence, which contributes to chronic adipose tissue inflammation in old age. Specific Aim 3 will define a role for γδ T cells in age-related metabolic dysfunction through PPARγ suppression. These studies will utilize aged mice genetically deficient in γδ T cells and mice that lack the cytokine IL- 17A, as well as various in vivo, ex vivo, and in vitro approaches. Collectively, this project will establish the novel concept that VAT-resident γδ T cells are drivers of chronic inflammation and adipose tissue dysfunction in the aged, and will elucidate mechanisms underlying these processes. As aging poses the greatest risk for the development of chronic conditions, the generated data will aid in the identification of strategies to reduce the burden of a long list of age- related disorders, for which chronic inflammation is a common denominator.