title: Acquisition of direct antiviral effector functions by CMV-specific CD4+ T lymphocytes with cellular maturation.
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.
authors.affiliation: Immunology Laboratory, Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Casazza
authors.forename: Michael R
authors.initials: MR
authors.lastname: Betts
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Precopio
authors.forename: Laura E
authors.initials: LE
authors.lastname: Ruff
authors.forename: Jason M
authors.initials: JM
authors.lastname: Brenchley
authors.forename: Brenna J
authors.initials: BJ
authors.lastname: Hill
authors.forename: Mario
authors.initials: M
authors.lastname: Roederer
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D018959:CD57 Antigens / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D054407:Chemokine CCL4; D003587:Cytomegalovirus / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D015683:Gene Products, gag / Q000276:immunology; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014616:Vaccinia virus / Q000276:immunology
chemical_list: D018959:CD57 Antigens; D054407:Chemokine CCL4; D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D052118:Lysosomal-Associated Membrane Protein 1; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D023201:CD40 Ligand; D007371:Interferon-gamma; D053804:Granzymes