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

J Immunol. 2011 Sep 1;187(5):2093-100. doi: 10.4049/jimmunol.1100978. Epub 2011 Jul 25.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Blotting, Western
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / immunology
  • Cell Separation
  • Cellular Senescence / immunology*
  • Flow Cytometry
  • Humans
  • Immunologic Memory / immunology
  • In Situ Hybridization, Fluorescence
  • Leukocyte Common Antigens / biosynthesis
  • Leukocyte Common Antigens / immunology
  • Lymphocyte Activation / immunology*
  • Middle Aged
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / immunology
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology*
  • Telomerase / immunology*
  • Telomerase / metabolism
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / biosynthesis
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / immunology
  • p38 Mitogen-Activated Protein Kinases / immunology
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • p38 Mitogen-Activated Protein Kinases
  • Telomerase
  • Leukocyte Common Antigens