Reversible senescence in human CD4+CD45RA+CD27- memory T cells

Di Mitri, Diletta, Azevedo, Rita I., Henson, Sian M., Libri, Valentina, Riddell, Natalie E., Macaulay, Richard, Kipling, David, Soares, Maria V. D., Battistini, Luca and Akbar, Arne N. 2011. Reversible senescence in human CD4+CD45RA+CD27- memory T cells. The Journal of Immunology 187 (5) , pp. 2093-2100. 10.4049/jimmunol.1100978

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Abstract

Persistent viral infections and inflammatory syndromes induce the accumulation of T cells with characteristics of terminal differentiation or senescence. However, the mechanism that regulates the end-stage differentiation of these cells is unclear. Human CD4+ effector memory (EM) T cells (CD27−CD45RA−) and also EM T cells that re-express CD45RA (CD27−CD45RA+; EMRA) have many characteristics of end-stage differentiation. These include the expression of surface KLRG1 and CD57, reduced replicative capacity, decreased survival, and high expression of nuclear γH2AX after TCR activation. A paradoxical observation was that although CD4+ EMRA T cells exhibit defective telomerase activity after activation, they have significantly longer telomeres than central memory (CM)-like (CD27+CD45RA−) and EM (CD27−CD45RA−) CD4+ T cells. This suggested that telomerase activity was actively inhibited in this population. Because proinflammatory cytokines such as TNF-α inhibited telomerase activity in T cells via a p38 MAPK pathway, we investigated the involvement of p38 signaling in CD4+ EMRA T cells. We found that the expression of both total and phosphorylated p38 was highest in the EM and EMRA compared with that of other CD4+ T cell subsets. Furthermore, the inhibition of p38 signaling, especially in CD4+ EMRA T cells, significantly enhanced their telomerase activity and survival after TCR activation. Thus, activation of the p38 MAPK pathway is directly involved in certain senescence characteristics of highly differentiated CD4+ T cells. In particular, CD4+ EMRA T cells have features of telomere-independent senescence that are regulated by active cell signaling pathways that are reversible.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	Q Science > QR Microbiology > QR180 Immunology
Publisher:	American Association of Immunologists
ISSN:	0022-1767
Last Modified:	04 Jun 2017 03:58
URI:	https://orca.cardiff.ac.uk/id/eprint/29879

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