Altered Function of Aging CD8+ T Cells Linked to Stress-Sensing Sestrins

Research by Dr. Arne Akbar and colleagues has shown that NK cell-like behavior of aging CD8+ T cells is linked to the expression of sestrins.

Chemicals resting in beakers on a laboratory bench.

As the immune system ages, the phenotype and activity of important immune cell populations is altered. In particular, aging CD8+ T cells exhibit considerable changes in gene expression that influence their metabolism and ability to provide protection against cancer or infectious diseases.

A recent publication in Nature Immunology, “Sestrins induce natural killer function in senescent-like CD8+ T cells,” explored the significance of sestrins, a family of stress-sensing proteins that contribute to the regulation of metabolism, to alterations in the function of aging CD8+ T cells from antigen-specific TCR-dependent killing to non-specific responses dependent on natural killer (NK) cell receptors.

The publication was authored by the research group of Dr. Arne Akbar, PhD, of University College London.

“My research group has been investigating mechanisms involved in alterations in T lymphocytes as they differentiate towards an end stage. Our hypothesis is that some of these changes may be reversible,” Dr. Akbar told ImmunoFrontiers.

“We investigated peripheral blood T lymphocytes from healthy individuals and performed multiparameter flow cytometry to identify different populations of cells, including single cell RNAseq to identify differences in gene expression between them. In addition, transductions studies were performed to silence the activity of certain molecules in particular the sestrins. Our results in humans on the role of sestrins were confirmed in sestrin knockout mice.”

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“The key discovery was that senescent CD8+ T cells downregulated T cell related signalling molecules while concomitantly expressing NK-related molecules, a process that is regulated by the sestrins.”

“We showed that senescent T cells that were considered to be dysfunctional and thus contributed to decreased immunity during aging instead have altered their functional profile, such that they no longer proliferate after encounter with antigen but can provide broad protective activity against tumour cells and infected cells. This can be reversed by blocking the sestrins that makes these cells respond to antigen while reducing NK activity.”

“We will now extend these studies to senescent CD4+ T cells and also to investigate CD8+ T cells that are responsive to persistent viral antigens like cytomegalovirus. The hypothesis is that these cells that are repeatedly activated in vivo and therefore become senescent, now behave more like NK cells, especially in older subjects,” Dr. Akbar continued.

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Thus, while repeated antigen exposure throughout CD8+ T cell aging can contribute to the development of senescent clones with a reduced dependence on TCR signalling, this change may be reversible. These findings complement recent research from the Technical University of Munich evaluating changes to the TCR repertoire of CD8+ T cells during conditions of chronic antigen exposure, such as during cytomegalovirus infection.

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Dr. Akbar’s take-home message for readers: “Senescence in human T cells is actively maintained, and senescent T cells can be manipulated to enhance T cell dependent function temporarily, such as to boost vaccine efficacy during aging.”