Senescence of T Lymphocytes: Implications for Enhancing Human Immunity

Abstract

As humans live longer, a central concern is to find ways to maintain their health as they age. Immunity declines during ageing, as shown by the increased susceptibility to infection by both previously encountered and new pathogens and by the decreased efficacy of vaccination. It is therefore crucial to understand the mechanisms responsible for this decrease in immunity and to develop new strategies to enhance immune function in older humans. We discuss here how the induction of senescence alters leukocyte, and specifically T cell, function. An emerging concept is that senescence and nutrient sensing-signalling pathways within T cells converge to regulate functional responses, and the manipulation of these pathways may offer new ways to enhance immunity during ageing.

Senescence mirrors the extent of liver fibrosis in chronic hepatitis C virus infection

“…In contrast to drug‐induced fibrosis, in viral hepatitis the infiltration of T‐cells plays an important role in disease progression. Since senescence may also occur in the immune system, we investigated senescence of T‐cells in liver tissues of patients with chronic HCV infection and different fibrosis stages. For this purpose, we performed double staining for the T‐cell marker CD3 and different senescence markers, ie, p‐HP1γ, p16 and p27 (Figure B).…”

“…The persistent activation of immune cells in chronic infection has been also linked to impairment of T‐cell function, commonly called T‐cell exhaustion . In addition, proinflammatory regulators, such as IFNα or p38, can inhibit telomerase, leading to enhanced telomere shortening and senescence . Finally, it was argued that chronic inflammation triggers oxidative stress, which causes DNA damage, telomere dysfunction and cellular senescence .…”

Successful and Maladaptive T Cell Aging

“…TEMRA T cells have low proliferative potential, short telomeres, and low telomerase activity and are considered to be senescent. Akbar et al (2016) have proposed a senescence model for TEMRAs that centers on the disproportionate activation of the p38 MAPK pathway (Figure 3). p38 phosphorylation occurs downstream of ATM and ROS through TAB1/AMPK activation rather than TCR signaling (Lanna et al, 2014).…”

Mitochondria in Cell Senescence: Is Mitophagy the Weakest Link?

“…Frequencies in excess of 5%, and sometimes as much as 20% and more, have been reported in tissues from old animals both with high (white blood cells (Akbar et al, 2016); crypt enterocytes (Jurk et al, 2014, Wang et al, 2009)) and low (dermal fibroblasts (Dimri et al, 1995), hepatocytes (Jurk et al, 2014, Wang et al, 2009), fat progenitors (Schafer et al, 2016), osteocytes (Farr et al, 2016)) proliferation rates as well as in postmitotic tissues (neurons (Jurk et al, 2012)). The rate of accumulation of senescent cells in liver and intestinal crypts predicts median and maximum lifespan of mice in cohorts with widely different aging rates (e.g.…”