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

Diletta Di Mitri, Rita I. Azevedo, Sian M. Henson, Valentina Libri, Natalie E. Riddell, Richard Macaulay, David Kipling, Maria V D Soares, Luca Battistini, Arne N. Akbar

Research output: Contribution to journalArticlepeer-review


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+ EMRAT 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+ EMRAT 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.

Original languageEnglish
Pages (from-to)2093-2100
Number of pages8
JournalJournal of Immunology
Issue number5
Publication statusPublished - Sep 1 2011

ASJC Scopus subject areas

  • Immunology


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