Invariant natural killer T cells coordinate removal of senescent cells

BackgroundThe failure of immune surveillance to remove senescent cells drives age-related diseases. Here, we target an endogenous immune surveillance mechanism that can promote elimination of senescent cells and reverse disease progression.MethodsWe identify a class of lipid-activated T cells,invariant natural killer T cells (iNKTs), that are involved in the removal of pathologic senescent cells. We use two disease models in which senescent cells accumulate to test whether activation of iNKT cells was sufficient to eliminate senescent cells in vivo.FindingsSenescent preadipocytes accumulate in white adipose tissue of chronic high-fat diet (HFD)-fed mice, and activation of iNKT cells with the prototypical glycolipid antigen alpha-galactosylceramide (αGalCer) led to a reduction of these cells with improved glucose control. Similarly, senescent cells accumulate within the lungs of mice injured by inhalational bleomycin, and αGalCer-induced activation of iNKT cells greatly limited this accumulation, decreased the lung fibrosis, and improved survival. Furthermore, co-culture experiments showed that the preferential cytotoxic activity of iNKT cells to senescent cells is conserved in human cells.ConclusionsThese results uncover a senolytic capacity of tissue-resident iNKT cells and pave the way for anti-senescence therapies that target these cells and their mechanism of activation.FundingThis work was supported by a grant from NIH and the UCSF Diabetes Center Funds.