Acquisition of direct antiviral effector functions by CMV-specific CD4+ T lymphocytes with cellular maturation

J Exp Med. 2006 Dec 25;203(13):2865-77. doi: 10.1084/jem.20052246. Epub 2006 Dec 11.

Abstract

The role of CD4+ T cells in the control of persistent viral infections beyond the provision of cognate help remains unclear. We used polychromatic flow cytometry to evaluate the production of the cytokines interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-2, the chemokine macrophage inflammatory protein (MIP)-1beta, and surface mobilization of the degranulation marker CD107a by CD4+ T cells in response to stimulation with cytomegalovirus (CMV)-specific major histocompatibility complex class II peptide epitopes. Surface expression of CD45RO, CD27, and CD57 on responding cells was used to classify CD4+ T cell maturation. The functional profile of virus-specific CD4+ T cells in chronic CMV infection was unique compared with that observed in other viral infections. Salient features of this profile were: (a) the simultaneous production of MIP-1beta, TNF-alpha, and IFN-gamma in the absence of IL-2; and (b) direct cytolytic activity associated with surface mobilization of CD107a and intracellular expression of perforin and granzymes. This polyfunctional profile was associated with a terminally differentiated phenotype that was not characterized by a distinct clonotypic composition. Thus, mature CMV-specific CD4+ T cells exhibit distinct functional properties reminiscent of antiviral CD8+ T lymphocytes.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD40 Ligand / metabolism
  • CD57 Antigens / immunology
  • Cell Differentiation / immunology*
  • Chemokine CCL4
  • Cytomegalovirus / immunology*
  • Cytotoxicity, Immunologic / immunology*
  • Epitopes, T-Lymphocyte / immunology
  • Female
  • Gene Products, gag / immunology
  • Granzymes / metabolism
  • Humans
  • Interferon-gamma / metabolism
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Lymphocyte Activation / immunology
  • Lysosomal-Associated Membrane Protein 1 / metabolism
  • Macrophage Inflammatory Proteins / metabolism
  • Male
  • Membrane Glycoproteins / metabolism
  • Middle Aged
  • Perforin
  • Pore Forming Cytotoxic Proteins / metabolism
  • T-Cell Antigen Receptor Specificity / immunology
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / immunology
  • Tumor Necrosis Factor-alpha / metabolism
  • Vaccinia virus / immunology

Substances

  • CD57 Antigens
  • Chemokine CCL4
  • Epitopes, T-Lymphocyte
  • Gene Products, gag
  • Lysosomal-Associated Membrane Protein 1
  • Macrophage Inflammatory Proteins
  • Membrane Glycoproteins
  • Pore Forming Cytotoxic Proteins
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • Tumor Necrosis Factor-alpha
  • Perforin
  • CD40 Ligand
  • Interferon-gamma
  • Granzymes