Invariant natural killer T cells coordinate removal of senescent cells

Shivani Arora,Peter J Thompson,Yao Wang,Aritra Bhattacharyya,Hara Apostolopoulou,Rachel Hatano,Ram P Naikawadi,Ajit Shah,Paul J Wolters,Suneil Koliwad,Mallar Bhattacharya,Anil Bhushan

doi:10.1016/j.medj.2021.04.014

Shivani Arora, Peter J Thompson + Show 10 more

Open Access

https://doi.org/10.1016/j.medj.2021.04.014

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Abstract

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. 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. 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. 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.

Highlights

The accumulation of senescent cells within tissues can drive the progression of diseases.[1,2] While removal of senescent cells with senolytic drugs has emerged as a promising therapeutic approach, the ubiquitous target of these drugs makes clinical applications challenging
In two different senescence-associated disease models, activation of invariant natural killer T cells (iNKTs) cells was sufficient to eliminate senescent cells in vivo and confer disease improvement. These results uncover a senolytic capacity of tissue-resident iNKT cells and pave the way for antisenescence therapies that target these cells and their mechanism of activation
Consistent with the upregulation of CD1d on senescent preadipocytes in vitro (Figure S1C), we found CD1d expression was increased in preadipocytes isolated from high-fat diet (HFD)-fed mice compared to chow mice (Figure 1D)

Summary

Introduction

The accumulation of senescent cells within tissues can drive the progression of diseases.[1,2] While removal of senescent cells with senolytic drugs has emerged as a promising therapeutic approach, the ubiquitous target of these drugs makes clinical applications challenging. Senescent preadipocytes were reported to accumulate in the white adipose tissue (WAT) of both mice chronically fed a HFD4 and in obese humans.[5] Genetic ablation (of p16Ink4a-expressing cells) or use of senolytic compounds resulted in Context and significance Failure of endogenous immune surveillance mechanisms to remove senescent cells drives the progression of diseases. In two different senescence-associated disease models, activation of iNKT cells was sufficient to eliminate senescent cells in vivo and confer disease improvement. These results uncover a senolytic capacity of tissue-resident iNKT cells and pave the way for antisenescence therapies that target these cells and their mechanism of activation

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