The Role of Gamma Delta - T Cells in Age-Associated Adipose Tissue Inflammation

In aging, chronic inflammation originating from adipose tissue, even in the absence of obesity, is strongly linked to the development of cardiometabolic disorders(1-5). Accumulation of senescent preadipocytes is among the central factors underlying this phenomenon; however, the specific events that promote preadipocyte senescence are not well understood. We recently discovered that the population of a specific subset of T cells, gamma delta (ãä)-T cells, is increased more than 5-fold in visceral adipose tissue (VAT) of aged mice; the accumulation of these cells, which comprise up to 30% of resident immune cells, was found only in visceral adipose depots(6). ãä-T cells are unique and understudied cells which act as innate responders(7-9), but their role in VAT inflammation is largely unknown. We determined that ãä-T cells in aged VAT are tissue-resident ãäT17 cells(6). Further, we confirmed an age-dependent increase of ãä-T cells in human VAT. Our data show that IL-6 levels in the circulation and VAT are reduced in aged mice lacking ãä-T cells (T cell receptor delta knockout, TCRä-/-) and that secretion of IL-6 and IL-17A in response to ex vivo stimulation is reduced in VAT explants lacking ãä-T cells. Moreover, these mice exhibit an improved metabolic phenotype and have lower levels of senescent cell markers p16Ink4a and Notch 3. These data provide strong evidence that ãä-T cells are mediators of age-related VAT inflammation. Based on these novel findings, we hypothesize that the accumulation of ãä-T cells in VAT promotes preadipocyte senescence and chronic inflammation in the aged. The following experiments will be conducted under an R56 Award to establish feasibility for key experiments that were originally proposed under the R01 application. Aim 1: To confirm feasibility of adipose tissue transplant from wild-type (TCRä+/+) to TCRä-/- mice. Aim 2: To establish parabiotic pairs of TCRä+/+ and TCRä-/- mice. Aim 3: To determine the viability of injected ãä-T cells in adoptive transfer experiments. Aim 4: To evaluate the abundance and phenotype of ãä-T cells in IL-17A deficient mice.