Reversible Senescence in Human CD4+CD45RA+CD27− Memory T Cells

Unlike cellular senescence in a strict sense, these functional deficits are reversed by inhibiting p38.

“Unlike cellular senescence in a strict sense, these functional deficits are reversed by inhibiting p38”

Unlike senescent fibroblasts, T cells with characteristics of senescence are prone to apoptosis in vitro.

“Unlike senescent fibroblasts however, T cells that have characteristics of senescence are prone to apoptosis in vitro [23, 28] although they may be induced to persist by appropriate signals such as growth factors in vivo [32].”

Senescent-like T cells can be identified by surface marker expression CD27-, CD28-, CD45RA+, KLRG1+, CD57+, which are characteristics of highly differentiated T cells.

“These cells can be identified by surface marker expression (CD27 - ,CD28 - , CD45RA + , KLRG1 + , CD57 + ) that are all characteristics of highly differentiated T cells [23, 28, 30, 31].”

Within primary human T cells, both CD4+ and CD8+ populations contain a subset of poorly proliferative cells with characteristics very similar to senescent fibroblasts.

“Within primary human T cells, in both CD4 + [23, 28, 29] and CD8 + [25, 30] populations, there is a subset of poorly proliferative cells that exhibit characteristics that are very similar to senescent fibroblasts (Fig. 1).”

Using small molecule inhibitors or specific inhibitory shRNA, p38 inhibition reconstituted proliferation and telomerase activity in T cells after activation.

“Using small molecule inhibitors [23, 30] or specific inhibitory shRNA [24] it was found that p38 inhibition reconstituted proliferation and also telomerase activity in T cells after activation.”

Based on in vitro data, blocking agents to p38 could be used in vivo to enhance certain T cell functions.

“One target for reversing senescence in T cells would be the p38 MAP kinase pathway and based on data that has been obtained in vitro , blocking agents to p38 could be used in vivo to enhance certain T cell functions [23-25, 30] .”

Alterations in T-cell activation in healthy elderly may result from accumulation of memory T cells.

“Alterations in T-cell activation in the healthy elderly may also result from accumulation of memory T cells [143, 144].”

In T cells, what has been called senescence can be reversed by p38 MAP kinase inhibitors.

“However there is evidence, certainly in T cells, that what has been defined as senescence can be reversed with the addition of p38 MAP kinase inhibitors, begging the question if this is proper senescence or indeed if senescence is not always a state of permanent cell cycle arrest (12).”

A block at the level of p38-MAPK by sestrins causes age-related signaling defects in effector and memory CD45RA+/CCR7− T cells.

“For example, a block at the level of p38-MAPK by sestrins causes age-related signaling defects in effector and memory CD45RA+/CCR7− T cells (195, 196).”