title: Defining the directionality and quality of influenza virus-specific CD8+ T cell cross-reactivity in individuals infected with hepatitis C virus.
abstract: Cross-reactivity of murine and recently human CD8(+) T cells between different viral peptides, i.e., heterologous immunity, has been well characterized. However, the directionality and quality of these cross-reactions is critical in determining their biological importance. Herein we analyzed the response of human CD8(+) T cells that recognize both a hepatitis C virus peptide (HCV-NS3) and a peptide derived from the influenza neuraminidase protein (Flu-NA). To detect the cross-reactive CD8(+) T cells, we used peptide-MHC class I complexes (pMHCs) containing a new mutant form of MHC class I able to bind CD8 more strongly than normal MHC class I complexes. T cell responses against HCV-NS3 and Flu-NA peptide were undetectable in normal donors. In contrast, some responses against the Flu-NA peptide were identified in HCV(+) donors who showed strong HCV-NS3-specific reactivity. The Flu-NA peptide was a weak agonist for CD8(+) T cells in HCV(+) individuals on the basis of novel pMHCs and functional assays. These data support the idea of cross-reactivity between the 2 peptides, but indicate that reactivity toward the Flu-NA peptide is highly CD8-dependent and occurs predominantly after priming during HCV infection. Our findings indicate the utility of the novel pMHCs in dissecting cross-reactivity and suggest that cross-reactivity between HCV and influenza is relatively weak. Further studies are needed to relate affinity and functionality of cross-reactive T cells.
authors.affiliation: Partners AIDS Research Center and Infectious Disease Division, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Kasprowicz
authors.forename: Scott M
authors.initials: SM
authors.lastname: Ward
authors.forename: Alison
authors.initials: A
authors.lastname: Turner
authors.forename: Alexandros
authors.initials: A
authors.lastname: Grammatikos
authors.forename: Brian E
authors.initials: BE
authors.lastname: Nolan
authors.forename: Lia
authors.initials: L
authors.lastname: Lewis-Ximenez
authors.forename: Charles
authors.initials: C
authors.lastname: Sharp
authors.forename: Jenny
authors.initials: J
authors.lastname: Woodruff
authors.forename: Vicki M
authors.initials: VM
authors.lastname: Fleming
authors.forename: Stuart
authors.initials: S
authors.lastname: Sims
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
authors.forename: Georg M
authors.initials: GM
authors.lastname: Lauer
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003429:Cross Reactions; D006526:Hepatitis C / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D009439:Neuraminidase / Q000276:immunology; D009975:Orthomyxoviridae / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000276:immunology; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D015395:Histocompatibility Antigens Class I; D009439:Neuraminidase; D014763:Viral Matrix Proteins; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases