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T lymphocyte depletion ameliorates age-related metabolic impairments in mice

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Both glucose tolerance and adaptive immune function exhibit significant age-related alterations. The influence of the immune system on obesity-associated glucose intolerance is well characterized; however, whether the immune system contributes to age-related glucose intolerance is not as well understood. Here, we report that advancing age results in an increase in T cell infiltration in the epididymal white adipose tissue (eWAT), liver, and skeletal muscle. Subtype analyses show that both CD4+, CD8+ T cells are greater with advancing age in each of these tissues and that aging results in a blunted CD4 to CD8 ratio. Anti-CD3 F(ab’)2 fragments depleted CD4+ and CD8+ cells in eWAT, CD4+ cells only in the liver, and did not deplete quadriceps T cells. In old mice, T cells producing both interferon-γ and tumor necrosis factor-α are accumulated in the eWAT and liver, and a greater proportion of skeletal muscle T cells produced interferon-γ. Aging resulted in increased proportion and numbers of T regulatory cells in eWAT, but not in the liver or muscle. Aging also resulted in greater numbers of eWAT and quadriceps CD206- macrophages and eWAT, liver and quadriceps B cells; neither cell type was altered by anti-CD3 treatment. Anti-CD3 treatment improved glucose tolerance in old mice and was accompanied by improved signaling related to liver and skeletal muscle insulin utilization and decreased gluconeogenesis-related gene expression in the liver. Our findings indicate a critical role of the adaptive immune system in the age-related metabolic dysfunction.

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This work was supported by the National Institutes of Health grants, K01 AG061271 (DWT), R01 AG060395 (AJD), and R01 AG048366 (LAL), and the Veteran’s Affairs Merit Review Award I01 BX004492 (LAL) from the US Department of Veterans Affairs Biomedical Laboratory Research and Development Service.

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Correspondence to Lisa A. Lesniewski.

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Trott, D.W., Islam, M.T., Buckley, D.J. et al. T lymphocyte depletion ameliorates age-related metabolic impairments in mice. GeroScience 43, 1331–1347 (2021).

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