Abstract 11105: Obesity Accelerates T Cell Senescence in Visceral Adipose Tissue

Abstract

Background: Age-related changes in the immune function, particularly T-cell immune-senescence likely contribute to the nature of chronic inflammation associated with ageing-related diseases. Recently, it becomes clear that T-cell immune-senescence is not due to dysregulation of the whole T cell population, but rather the accumulation of senescence-associated T-cells. The senescence-associated T-cells are memory phenotype (MP) T-cells that constitutively express programmed cell death 1 (PD-1) on their surface. Purpose: Obesity predisposes to a lower age of onset of ageing-related diseases. We examined whether obesity accelerates T-cell senescence in visceral adipose tissue (VAT), and if so, how this impacts on VAT inflammation and glucose metabolism. Results: HFD-induced obesity causes the phenotypic changes in CD4+ T-cells similar to those observed during chronological aging process, marked by a progress increase in the number of PD-1+ MP CD4+ T-cells highly resembling senescence-associated T cells. Unique features of adipose tissue PD-1+ MP CD4+ T-cells include; expression of myeloid lineage gene, attenuated TCR-mediated proliferation, a decreased ability to produce T-cell specific lymphokines on TCR stimulation, highly biased secretin of OPN, and a rise in the levels of DNA damage response markers as well as the cyclin-dependent kinase inhibitors. The PD-1+ MP CD4+ T-cells stimulated macrophage infiltration and promoted M1 macrophage polarization, while reducing regulatory T-cells in VAT. HFD-dependent conversion of naïve T cells to PD-1+ MP T-cells in VAT depends on macrophages and B cells. Immunological depletion of PD-1+ T-cells attenuated adipose inflammation and improved insulin resistance in diet-induced obese mice, while adoptive transfer of PD-1+ MP CD4+ T-cells in VAT induced adipose inflammation and insulin resistance in non-obese mice. Analysis of human tissue suggested that a similar process may also occur in human. Interestingly, T2DM patients had more abundant PD-1+ T-cells in omental adipose tissue than non-DM patients independently BMI and age. Conclusion: Increased visceral adiposity accelerates T-cell senescence and this, in turn, leads to chronic VAT inflammation and abnormal glucose metabolism.