T cell receptor-mediated activation is a potent inducer of macroautophagy in human CD8(+)CD28(+) T cells but not in CD8(+)CD28(-) T cells

Exp Gerontol. 2014 Jun;54:75-83. doi: 10.1016/j.exger.2014.01.018. Epub 2014 Jan 24.

Abstract

A key feature of the aged human immune system is the accumulation of highly differentiated CD8(+)CD28(-) T cells, a phenomenon that negatively influences immune function in the elderly. However, the mechanisms that regulate survival or death of CD8(+)CD28(-) T cells remain incompletely understood. Macroautophagy has been shown to protect cells from unfavorable environmental conditions and extend lifespan of various cells and organisms. In this study, we investigated autophagy in CD8(+)CD28(+) and CD8(+)CD28(-) T cells following T cell receptor (TCR) engagement. We demonstrate that TCR-mediated activation led to a potent induction of autophagy in CD8(+)CD28(+) T cells which was accompanied by an increased activity of the mammalian target of rapamycin complex 1 (mTORC1). This was surprising, as mTORC1 is generally perceived as an inhibitor of autophagy. Inhibition of mTORC1 by rapamycin could still enhance activation-induced autophagy. In contrast, CD8(+)CD28(-) T cells induced autophagy to a significantly lower extent in response to TCR engagement compared to CD8(+)CD28(+) T cells and failed to increase autophagy upon mTORC1 inhibition. In conclusion, we describe for the first time the induction of autophagy in human CD8(+) T cells following TCR engagement and the decreased ability of CD8(+)CD28(-) T cells to induce autophagy, suggesting that they cannot meet the metabolic needs of antigen receptor-mediated activation and are therefore unlikely to survive when confronted by their specific antigens.

Keywords: Aging; Autophagy; CD28; Human; T cells; mTOR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Autophagy / physiology*
  • CD28 Antigens / physiology*
  • CD8-Positive T-Lymphocytes / physiology*
  • Cells, Cultured
  • Female
  • Flow Cytometry
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Leukocytes, Mononuclear / physiology
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes / metabolism
  • Receptors, Antigen, T-Cell / physiology*
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • CD28 Antigens
  • Immunosuppressive Agents
  • Multiprotein Complexes
  • Receptors, Antigen, T-Cell
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Sirolimus