title: The functional profile of primary human antiviral CD8+ T cell effector activity is dictated by cognate peptide concentration.
abstract: Antiviral CD8(+) T cells can elaborate at least two effector functions, cytokine production and cytotoxicity. Which effector function is elaborated can determine whether the CD8(+) T cell response is primarily inflammatory (cytokine producing) or antiviral (cytotoxic). In this study we demonstrate that cytotoxicity can be triggered at peptide concentrations 10- to 100-fold less than those required for cytokine production in primary HIV- and CMV-specific human CD8(+) T cells. Cytolytic granule exocytosis occurs at peptide concentrations insufficient to cause substantial TCR down-regulation, providing a mechanism by which a CD8(+) T cell could engage and lyse multiple target cells. TCR sequence analysis of virus-specific cells shows that individual T cell clones can degranulate or degranulate and produce cytokine depending on the Ag concentration, indicating that response heterogeneity exists within individual CD8(+) T cell clonotypes. Thus, antiviral CD8(+) T cell effector function is determined primarily by Ag concentration and is not an inherent characteristic of a virus-specific CD8(+) T cell clonotype or the virus to which the response is generated. The inherent ability of viruses to induce high or low Ag states may be the primary determinant of the cytokine vs cytolytic nature of the virus-specific CD8(+) T cell response.
authors.affiliation: Immunology Laboratory, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. mbetta@mail.nih.gov
authors.forename: Michael R
authors.initials: MR
authors.lastname: Betts
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Jason M
authors.initials: JM
authors.lastname: Brenchley
authors.forename: Karin
authors.initials: K
authors.lastname: Loré
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Guenaga
authors.forename: Anna
authors.initials: A
authors.lastname: Smed-Sorensen
authors.forename: David R
authors.initials: DR
authors.lastname: Ambrozak
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Migueles
authors.forename: Mark
authors.initials: M
authors.lastname: Connors
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: D000941:Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D015550:Cell Degranulation / Q000276:immunology; D002469:Cell Separation; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis*; D003587:Cytomegalovirus / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D015497:HIV-1 / Q000276:immunology; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D010455:Peptides / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000502:physiology; D014764:Viral Proteins / Q000276:immunology / Q000378:metabolism*
chemical_list: D000941:Antigens; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins; D007371:Interferon-gamma