Dual roles of IL-15 in maintaining IL-7RalphalowCCR7- memory CD8+ T cells in humans via recovering the phosphatidylinositol 3-kinase/AKT pathway

J Immunol. 2007 Nov 15;179(10):6734-40. doi: 10.4049/jimmunol.179.10.6734.

Abstract

Recently, we identified two subsets of CCR7(-) memory CD8(+) T cells expressing high and low levels of the IL-7R alpha-chain (IL-7Ralpha) that is essential for memory T cell survival in human peripheral blood. IL-7Ralpha(low)CCR7(-) memory CD8(+) T cells that produce effector cytokines and perforin have impaired proliferation and survival in response to TCR triggering and IL-7, respectively. These findings raise a question of how such cells are sustained at significant numbers, >20% of peripheral CD8(+) T cells, despite impaired IL-7- and TCR-mediated cell maintenance. In this study, we demonstrate that IL-7Ralpha(low)CCR7(-) memory CD8(+) T cells have increased expression of IL-2/15R beta-chain (IL-2/15Rbeta), which is critical for IL-15 signaling, with enhanced gene expression of T box expressed in T cells (T-bet) and eomesodermin (eomes), transcriptional factors involved in IL-2/15Rbeta expression compared with IL-7Ralpha(high)CCR7(-) memory CD8(+) T cells. Such a cytokine chain is functional as IL-7Ralpha(low)CCR7(-) memory CD8(+) T cells proliferate considerably in response to IL-15. Furthermore, adding IL-15 to TCR triggering recovers impaired TCR-mediated proliferation of IL-7Ralpha(low) memory CD8(+) T cells via restoring the activation of the PI3K/AKT pathway. These findings indicate that IL-15 has dual roles in maintaining IL-7Ralpha(low)CCR7(-) memory CD8(+) T cells via TCR-dependent and -independent mechanisms. Moreover, IL-15 can be useful in reviving impaired proliferative function of such memory CD8(+) T cells with effector functions against infections and tumors via rescuing the PI3K/AKT pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes / enzymology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Proliferation
  • Cell Survival / physiology
  • Enzyme Activation / immunology
  • Gene Expression Regulation / immunology
  • Humans
  • Immunologic Memory / physiology*
  • Infections / enzymology
  • Infections / immunology
  • Interleukin-15 / immunology*
  • Interleukin-15 / metabolism
  • Interleukin-15 / pharmacology
  • Interleukin-2 Receptor beta Subunit
  • Interleukin-7 / immunology
  • Interleukin-7 / metabolism
  • Neoplasms / enzymology
  • Neoplasms / immunology
  • Perforin / immunology
  • Perforin / metabolism
  • Phosphatidylinositol 3-Kinases / immunology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / immunology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, CCR7*
  • Receptors, Interleukin-17 / biosynthesis
  • Receptors, Interleukin-17 / immunology*
  • Signal Transduction / immunology

Substances

  • CCR7 protein, human
  • IL17RA protein, human
  • IL7 protein, human
  • Interleukin-15
  • Interleukin-2 Receptor beta Subunit
  • Interleukin-7
  • Receptors, Antigen, T-Cell
  • Receptors, CCR7
  • Receptors, Interleukin-17
  • Perforin
  • Proto-Oncogene Proteins c-akt