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Journal of Virology, July 2007, p. 7608-7619, Vol. 81, No. 14
0022-538X/07/$08.00+0     doi:10.1128/JVI.02834-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Direct Ex Vivo Analyses of HLA-DR1 Transgenic Mice Reveal an Exceptionally Broad Pattern of Immunodominance in the Primary HLA-DR1-Restricted CD4 T-Cell Response to Influenza Virus Hemagglutinin{triangledown}

Katherine A. Richards,{dagger} Francisco A. Chaves,{dagger} Frederick R. Krafcik, David J. Topham, Christopher A. Lazarski, and Andrea J. Sant*

David H. Smith Center for Vaccine Biology and Immunology, Aab Institute, and Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642

Received 21 December 2006/ Accepted 2 May 2007

The recent threat of an avian influenza pandemic has generated significant interest in enhancing our understanding of the events that dictate protective immunity to influenza and in generating vaccines that can induce heterosubtypic immunity. Although antigen-specific CD4 T cells are known to play a key role in protective immunity to influenza through the provision of help to B cells and CD8 T cells, little is known about the specificity and diversity of CD4 T cells elicited after infection, particularly those elicited in humans. In this study, we used HLA-DR transgenic mice to directly and comprehensively identify the specificities of hemagglutinin (HA)-specific CD4 T cells restricted to a human class II molecule that were elicited following intranasal infection with a strain of influenza virus that has been endemic in U.S. human populations for the last decade. Our results reveal a surprising degree of diversity among influenza virus-specific CD4 T cells. As many as 30 different peptides, spanning the entire HA protein, were recognized by CD4 T cells, including epitopes genetically conserved among H1, H2, and H5 influenza A viruses. We also compared three widely used major histocompatibility class II algorithms to predict HLA-DR binding peptides and found these as yet inadequate for identifying influenza virus-derived epitopes. The results of these studies offer key insights into the spectrum of peptides recognized by HLA-DR-restricted CD4 T cells that may be the focus of immune responses to infection or to experimental or clinical vaccines in humans.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642. Phone: (585) 275-9798. Fax: (585) 273-2452. E-mail: andrea_sant{at}urmc.rochester.edu

{triangledown} Published ahead of print on 16 May 2007.

{dagger} These authors contributed equally to this work.

Journal of Virology, July 2007, p. 7608-7619, Vol. 81, No. 14
0022-538X/07/$08.00+0     doi:10.1128/JVI.02834-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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