title: Hierarchies in cytokine expression profiles for acute and resolving influenza virus-specific CD8+ T cell responses: correlation of cytokine profile and TCR avidity.
abstract: The development and resolution phases of influenza-specific CD8(+) T cell cytokine responses to epitopes derived from the viral nucleoprotein (D(b)NP(366)) and acid polymerase (D(b)PA(224)) were characterized in C57BL/6J mice for a range of anatomical compartments in the virus-infected lung and lymphoid tissue. Lymphocyte numbers were measured by IFN-gamma expression following stimulation with peptide, while the quality of the response was determined by the intensity of staining and the distribution of CD8(+) T cells producing TNF-alpha and IL-2. Both the levels of expression and the prevalence of TNF-alpha(+) and IL-2(+) cells reflected the likely Ag load, with clear differences being identified for populations from the alveolar space vs the lung parenchyma. Irrespective of the site or time of T cell recovery, IL-2(+) cells were consistently found to be a subset of the TNF-alpha(+) population which was, in turn, contained within the IFN-gamma(+) set. The capacity to produce IL-2 may thus be considered to reflect maximum functional differentiation. The hierarchy in cytokine expression throughout the acute phase of the primary and secondary response tended to be D(b)PA(224) > D(b)NP(366). Both elution studies with the cognate tetramers and experiments measuring CD8 beta coreceptor dependence for peptide stimulation demonstrated the same D(b)PA(224) > D(b)NP(366) profile for TCR avidity. Overall, the quality of any virus-specific CD8(+) T cell response appears variously determined by the avidity of the TCR-pMHC interaction, the duration and intensity of Ag stimulation characteristic of the particular tissue environment, and the availability of CD4(+) T help.
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, Parkville, Vic., Australia. nllg@unimelb.edu.au
authors.forename: Nicole L
authors.initials: NL
authors.lastname: La Gruta
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Turner
authors.forename: Peter C
authors.initials: PC
authors.lastname: Doherty
mesh_terms: D000208:Acute Disease; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D009980:Influenza A virus / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D012324:RNA-Dependent RNA Polymerase / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014758:Viral Core Proteins / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology
chemical_list: D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D007376:Interleukin-2; C061290:PA protein, influenza viruses; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha; D014758:Viral Core Proteins; D014764:Viral Proteins; C102366:nucleoprotein (366-374), influenza virus; D007371:Interferon-gamma; D012324:RNA-Dependent RNA Polymerase