Heterosubtypic immunity to influenza A virus infection requires a properly diversified antibody repertoire

Huan H. Nguyen, Michael Zemlin, Ivaylo I. Ivanov, Judit Andrasi, Cosima Zemlin, Huong L. Vu, Robert Schelonka, Harry W. Schroeder, Jiri Mestecky

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48 Scopus citations


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, ΔD-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 ΔD-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.

Original languageEnglish (US)
Pages (from-to)9331-9338
Number of pages8
JournalJournal of virology
Issue number17
StatePublished - Sep 2007
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology


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