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Journal of Virology, September 2007, p. 9331-9338, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.00751-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Heterosubtypic Immunity to Influenza A Virus Infection Requires a Properly Diversified Antibody Repertoire{triangledown}

Huan H. Nguyen,1* Michael Zemlin,2 Ivaylo I. Ivanov,2 Judit Andrasi,1 Cosima Zemlin,2 Huong L. Vu,1 Robert Schelonka,3 Harry W. Schroeder Jr.,1,2 and Jiri Mestecky1

Department of Microbiology,1 Division of Developmental and Clinical Immunology,2 Pediatrics-Neonatology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama 35294-21703

Received 5 April 2007/ Accepted 5 June 2007

Heterosubtypic immunity (HSI) is defined as cross-protection to infection with an influenza A virus serotype other than the one used for primary infection. Although HSI has been thought to be mediated by serotype cross-reactive cytotoxic T lymphocytes (CTL) that recognize conserved epitopes of structural proteins, recent studies suggest that antibodies (Abs) may make a significant contribution. In this study, we provide further evidence for the role of Abs in HSI using transgenic mice lacking terminal deoxyribonucleotidyltransferase (TdT), which adds N nucleotides to V-D and D-J junctions of the complementary determining region 3 (CDR3) (TdT–/–) and mice with altered Ab repertoires due to replacement of the complete locus of heavy chain diversity segments (DH) with an altered DH segment (namely, {Delta}D-iD). Both types of mice failed to generate complete HSI, although they were able to mount protective immunity to a homologous challenge. Lower levels of virus-specific antibodies along with more severely impaired HSI were observed in TdT–/– mice compared to those in {Delta}D-iD mice, while CTL activity remained unchanged in both types of mice. These findings indicate that a properly diversified antibody repertoire is required for HSI and that N addition by TdT is a more effective mechanism in the induction of a properly diversified antibody repertoire and, therefore, complete HSI. The results suggest that the diversity of the antibody repertoire as determined by the composition of the D region of HCDR3 and by N addition are among the mechanisms selected for in evolution to create a favorable environment to resolve infections with mutated viruses.

* Corresponding author. Present address: International Vaccine Institute, SNU Research Park, San 4-8, Bongcheon-7-dong, Kwanak-gu, Seoul 151-919, Korea. Phone: 82-2-881-1272. Fax: 82-2-881-1410. E-mail: hhnguyen{at}ivi.int

{triangledown} Published ahead of print on 13 June 2007.

Journal of Virology, September 2007, p. 9331-9338, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.00751-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Schelonka, R. L., Zemlin, M., Kobayashi, R., Ippolito, G. C., Zhuang, Y., Gartland, G. L., Szalai, A., Fujihashi, K., Rajewsky, K., Schroeder, H. W. Jr. (2008). Preferential Use of DH Reading Frame 2 Alters B Cell Development and Antigen-Specific Antibody Production. J. Immunol. 181: 8409-8415 [Abstract] [Full Text]  
  • Zemlin, M., Schelonka, R. L., Ippolito, G. C., Zemlin, C., Zhuang, Y., Gartland, G. L., Nitschke, L., Pelkonen, J., Rajewsky, K., Schroeder, H. W. Jr. (2008). Regulation of Repertoire Development through Genetic Control of DH Reading Frame Preference. J. Immunol. 181: 8416-8424 [Abstract] [Full Text]  


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