{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T11:21:38Z","timestamp":1778498498538,"version":"3.51.4"},"reference-count":70,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2011,9,1]],"date-time":"2011-09-01T00:00:00Z","timestamp":1314835200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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\u2212CD45RA\u2212) and also EM T cells that re-express CD45RA (CD27\u2212CD45RA+; 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 \u03b3H2AX 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\u2212) and EM (CD27\u2212CD45RA\u2212) CD4+ T cells. This suggested that telomerase activity was actively inhibited in this population. Because proinflammatory cytokines such as TNF-\u03b1 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.<\/jats:p>","DOI":"10.4049\/jimmunol.1100978","type":"journal-article","created":{"date-parts":[[2011,7,25]],"date-time":"2011-07-25T23:17:37Z","timestamp":1311635857000},"page":"2093-2100","source":"Crossref","is-referenced-by-count":212,"title":["Reversible Senescence in Human CD4+CD45RA+CD27\u2212 Memory T Cells"],"prefix":"10.1093","volume":"187","author":[{"given":"Diletta","family":"Di Mitri","sequence":"first","affiliation":[{"name":"Division of Infection and Immunity, University College London , London W1T 4JF ,","place":["United Kingdom"]},{"name":"Neuroimmunology Unit, Santa Lucia Foundation , Rome 00143 ,","place":["Italy"]}]},{"given":"Rita I","family":"Azevedo","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, University College London , London W1T 4JF ,","place":["United Kingdom"]},{"name":"Unidade de Imunologia Clinica, Instituto de Medicina Molecular , Lisboa 1649-028 ,","place":["Portugal"]}]},{"given":"Sian M","family":"Henson","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, University College London , London W1T 4JF ,","place":["United Kingdom"]}]},{"given":"Valentina","family":"Libri","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, University College London , London W1T 4JF ,","place":["United Kingdom"]}]},{"given":"Natalie E","family":"Riddell","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, University College London , London W1T 4JF ,","place":["United Kingdom"]}]},{"given":"Richard","family":"Macaulay","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, University College London , London W1T 4JF ,","place":["United Kingdom"]}]},{"given":"David","family":"Kipling","sequence":"additional","affiliation":[{"name":"School of Medicine, Cardiff University , Heath Park, Cardiff CF14 4XN ,","place":["United Kingdom"]}]},{"given":"Maria V D","family":"Soares","sequence":"additional","affiliation":[{"name":"Unidade de Citometria de Fluxo, Instituto de Medicina Molecular , Lisboa 1649-028 ,","place":["Portugal"]}]},{"given":"Luca","family":"Battistini","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Santa Lucia Foundation , Rome 00143 ,","place":["Italy"]}]},{"given":"Arne N","family":"Akbar","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, University College London , London W1T 4JF ,","place":["United Kingdom"]}]}],"member":"286","published-online":{"date-parts":[[2011,9,1]]},"reference":[{"key":"2025032410311677800_r1","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1146\/annurev.immunol.22.012703.104702","article-title":"Central memory and effector memory T cell subsets: function, generation, and maintenance","volume":"22","author":"Sallusto","year":"2004","journal-title":"Annu. 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