Defining the directionality and quality of influenza virus-specific CD8+ T cell cross-reactivity in individuals infected with hepatitis C virus

• Published in: The Journal of clinical investigation Vol. 118; no. 3; pp. 1143 - 1153
• Main Authors: Kasprowicz, Victoria, Ward, Scott M, Turner, Alison, Grammatikos, Alexandros, Nolan, Brian E, Lewis-Ximenez, Lia, Sharp, Charles, Woodruff, Jenny, Fleming, Vicki M, Sims, Stuart, Walker, Bruce D, Sewell, Andrew K, Lauer, Georg M, Klenerman, Paul
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.03.2008
• Subjects: CD8-Positive T-Lymphocytes - immunology; Cross Reactions; Hepatitis C - immunology; Histocompatibility Antigens Class I - immunology; Humans; Neuraminidase - immunology; Orthomyxoviridae - immunology; Viral Matrix Proteins - immunology; Viral Nonstructural Proteins - immunology
• ISSN: 0021-9738
• DOI: 10.1172/JCI33082

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.