title: Heterosubtypic immunity to influenza A virus infection requires a properly diversified antibody repertoire.
abstract: 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 (D(H)) with an altered D(H) 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.
authors.affiliation: Department of Microbiology, The University of Alabama at Birmingham, Birmingham, Alabama 35294-2170, USA. hhnguyen@ivi.int
authors.forename: Huan H
authors.initials: HH
authors.lastname: Nguyen
authors.forename: Michael
authors.initials: M
authors.lastname: Zemlin
authors.forename: Ivaylo I
authors.initials: II
authors.lastname: Ivanov
authors.forename: Judit
authors.initials: J
authors.lastname: Andrasi
authors.forename: Cosima
authors.initials: C
authors.lastname: Zemlin
authors.forename: Huong L
authors.initials: HL
authors.lastname: Vu
authors.forename: Robert
authors.initials: R
authors.lastname: Schelonka
authors.forename: Harry W
authors.initials: HW
authors.lastname: Schroeder
authors.forename: Jiri
authors.initials: J
authors.lastname: Mestecky
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D001835:Body Weight; D003429:Cross Reactions; D004253:DNA Nucleotidylexotransferase / Q000172:deficiency; D004195:Disease Models, Animal; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D009980:Influenza A virus / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D017384:Sequence Deletion; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D007143:Immunoglobulin Heavy Chains; D011948:Receptors, Antigen, T-Cell; D004253:DNA Nucleotidylexotransferase