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Published on: October 29, 2015
Invariant Natural Killer T cells coordinate removal of senescent cells
Shivani Arora1, Peter J Thompson1, Yao Wang1
1Diabetes Center, University of California San Francisco, San Francisco CA, USA 94143.
Background:
The failure of immune surveillance to remove senescent cells drive age-related diseases. Here, we target an endogenous immune surveillance mechanism that can promote elimination of senescent cells and reverse disease progression.
Methods:
We identify a class of lipid-activated T cells, invariant natural killer T cells (iNKTs) 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.
Findings:
Senescent 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.
Conclusions:
These 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.
Insights
Invariant natural killer T cells (iNKTs) eliminate senescent cells, reversing age-related disease progression. Activating iNKTs clears senescent cells, offering a novel senolytic therapy approach.
Area of Science:
- Immunology
- Cellular Senescence
- Aging Research
Background:
- Failure of immune surveillance to clear senescent cells contributes to age-related diseases.
- Senescent cells accumulate in tissues, driving disease progression.
- Targeting endogenous immune mechanisms offers a therapeutic strategy.
Purpose of the Study:
- To investigate the role of invariant natural killer T cells (iNKTs) in clearing senescent cells.
- To determine if iNKT cell activation can reverse age-related disease progression.
- To explore iNKT cells as a potential senolytic therapy.
Main Methods:
- Identification of iNKT cells as key players in senescent cell removal.
- Utilizing two disease models with senescent cell accumulation (high-fat diet, bleomycin injury).
- Activation of iNKT cells using alpha-galactosylceramide (αGalCer) in vivo and in vitro.
Main Results:
- iNKT cell activation reduced senescent preadipocytes in mice on a high-fat diet, improving glucose control.
- iNKT cell activation limited senescent cell accumulation in bleomycin-injured mouse lungs, reducing fibrosis and improving survival.
- Human cell co-cultures confirmed iNKT cells' preferential cytotoxic activity against senescent cells.
Conclusions:
- Tissue-resident iNKT cells possess senolytic capacity.
- iNKT cell activation is a viable strategy to eliminate senescent cells.
- This research opens avenues for novel anti-senescence therapies targeting iNKT cells.
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