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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<jats:sup>\u2212\/\u2212<\/jats:sup>) and mice with altered Ab repertoires due to replacement of the complete locus of heavy chain diversity segments (D<jats:sub>H<\/jats:sub>) with an altered D<jats:sub>H<\/jats:sub>segment (namely, \u0394D-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<jats:sup>\u2212\/\u2212<\/jats:sup>mice compared to those in \u0394D-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.<\/jats:p>","DOI":"10.1128\/jvi.00751-07","type":"journal-article","created":{"date-parts":[[2007,6,14]],"date-time":"2007-06-14T04:04:37Z","timestamp":1181793877000},"page":"9331-9338","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":50,"title":["Heterosubtypic Immunity to Influenza A Virus Infection Requires a Properly Diversified Antibody Repertoire"],"prefix":"10.1128","volume":"81","author":[{"given":"Huan H.","family":"Nguyen","sequence":"first","affiliation":[{"name":"Department of Microbiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Zemlin","sequence":"additional","affiliation":[{"name":"Division of Developmental and Clinical Immunology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivaylo I.","family":"Ivanov","sequence":"additional","affiliation":[{"name":"Division of Developmental and Clinical Immunology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judit","family":"Andrasi","sequence":"additional","affiliation":[{"name":"Department of Microbiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cosima","family":"Zemlin","sequence":"additional","affiliation":[{"name":"Division of Developmental and Clinical Immunology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huong L.","family":"Vu","sequence":"additional","affiliation":[{"name":"Department of Microbiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Schelonka","sequence":"additional","affiliation":[{"name":"Pediatrics-Neonatology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama 35294-2170"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Harry W.","family":"Schroeder","sequence":"additional","affiliation":[{"name":"Department of Microbiology"},{"name":"Division of Developmental and Clinical Immunology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiri","family":"Mestecky","sequence":"additional","affiliation":[{"name":"Department of Microbiology"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.79.13.4118"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.5.2250"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.192.2.271"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.12.7437"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.4.2453"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830260943"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.1997.tb01010.x"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0264-410X(99)00005-5"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/1074-7613(95)90068-3"},{"key":"e_1_3_2_11_2","first-page":"235","year":"1996","unstructured":"Gerhard, W., K. 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