Ectonucleotidase CD38 demarcates regulatory, memory-like CD8+ T cells with IFN-γ-mediated suppressor activities

PLoS One. 2012;7(9):e45234. doi: 10.1371/journal.pone.0045234. Epub 2012 Sep 17.

Abstract

Regulatory CD8(+) T cells are critical for self-tolerance and restricting excessive immune responses. The variety of immune functions they fulfill, the heterogeneity of their phenotype, and the mechanism of action are still poorly understood. Here we describe that regulatory CD8(+) T cells exhibiting immunosuppressive actions in vitro and in vivo are recognized as CD38(high) T cells and present in naive mice. CD38 is a glycosylated membrane protein with ectonucleotidase properties. CD8(+)CD38(high) (CD44(+)CD122(+)CD62L(high)) lymphocytes suppress CD4(+) effector T-cell proliferation in an antigen-non specific manner via IFN-γ. While direct cell-to-cell contact is needed for this suppressor activity, it is independent of membrane-bound TGF-β and granzyme B release. IL-15 potentiates the suppressive activity of CD8(+)CD38(high) T cells and controls their survival and expansion. In humans CD8(+)CD38(high) T cells inhibit CD4(+) effector T cell proliferation. In vivo, CD8(+)CD38(high), but not CD8(+)CD38(-) T cells mitigate murine experimental autoimmune encephalomyelitis (EAE) by reducing the clinical score and delaying disease occurrence. EAE suppression is enhanced by pre-treatment of CD8(+)CD38(high) T cells with IL-15. These findings add evidence that the expression of ectoenzyme receptor family members positively correlates with suppressor functions and identifies CD8(+)CD38(high) T cells as potential inhibitors of excessive immune responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-ribosyl Cyclase 1 / immunology*
  • ADP-ribosyl Cyclase 1 / metabolism
  • Animals
  • Antigens, CD / immunology
  • Antigens, CD / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology*
  • Cell Communication / immunology
  • Cell Proliferation
  • Cell Survival
  • Cells, Cultured
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / pathology*
  • Female
  • Flow Cytometry
  • Immunologic Memory
  • Immunophenotyping
  • Interferon-gamma / immunology*
  • Interleukin-15 / immunology
  • Lymphocyte Activation
  • Membrane Glycoproteins / immunology*
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nucleotidases / immunology*
  • Nucleotidases / metabolism
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • T-Lymphocytes, Regulatory / pathology*

Substances

  • Antigens, CD
  • Interleukin-15
  • Membrane Glycoproteins
  • Interferon-gamma
  • Nucleotidases
  • nucleotidase
  • Cd38 protein, mouse
  • ADP-ribosyl Cyclase 1

Grant support

This work was supported by Seventh Framework Programme Inflacare: Health-2007-2.4.1-10 and by SFBTR22/A14. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.