Senescent T cells: Beneficial and detrimental roles

Abstract

As the thymus involutes during aging, the T-cell pool has to be maintained by the periodic expansion of preexisting T cells during adulthood. A conundrum is that repeated episodes of activation and proliferation drive the differentiation of T cells toward replicative senescence, due to telomere erosion. This review discusses mechanisms that regulate the end-stage differentiation (senescence) of T cells. Although these cells, within both CD4 and CD8 compartments, lose proliferative activity after antigen-specific challenge, they acquire innate-like immune function. While this may confer broad immune protection during aging, these senescent T cells may also cause immunopathology, especially in the context of excessive inflammation in tissue microenvironments.

Keywords: T cell; TEMRA; aging; senescence; terminally differentiated cell.

FIGURE 1

Schematic model for T cell differentiation during aging. Upon activation, naive T cells differentiate into several stages of memory and effector cells. The proliferative potential, telomere length, and telomerase activity are reduced upon differentiation across the lifetime. As age increase, the number of terminally differentiated cell TEMRA accumulates compared with other subsets. T cells lose the expression of costimulatory receptors CD27, CD28, and CD45RA as they differentiate from naïve to terminally differentiated cell. However, they regain expression of CD45RA when they reach an end‐stage and these (senescent) cells have limit replicative capacity but are highly cytotoxic and acquire NK‐related function.

FIGURE 2

Beneficial and detrimental roles of senescent T cells. (A) Senescent CD8⁺ T cells express NK cell receptors (NKR) such as NKG2C and NKG2D that recognize their ligands (NKR‐L) such as MICA/B that is expressed by on the senescent stromal cells, tumor cells, and and virally infected cells, that contributes to their clearance. (B) Overwhelming inflammatory cytokine production drives the ability of senescent T cells to recognize healthy tissue cells (e.g., epithelial, endothelial, muscle and immune cells) that are induced to express stimulatory NK ligands. This interaction may promote the aberrant killing in a nonspecific fashion and contribute to off‐target tissue pathology.