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We investigated the effect of viral dose on primary CD8+ T cell (TCD8+) ID by injecting mice i.p. with various doses of influenza A virus and assessing the primary TCD8+ response to five dominant and subdominant peptides. Increasing viral dose enhanced the overall strength of the TCD8+ response, and it altered the ID hierarchy: specifically, NP366\u2013374 TCD8+ were dominant at low viral doses but were supplanted by PA224\u2013233 TCD8+ at high doses. To understand the basis for this reversal, we mathematically modeled these TCD8+ responses and used Bayesian statistics to obtain estimates for Ag presentation, TCD8+ precursor numbers, and avidity. Interestingly, at low viral doses, Ag presentation most critically shaped ID hierarchy, enabling TCD8+ specific to the more abundantly presented NP366\u2013374 to dominate. By comparison, at high viral doses, TCD8+ avidity and precursor numbers appeared to be the major influences on ID hierarchy, resulting in PA224\u2013233 TCD8+ usurping NP366\u2013374 cells as the result of higher avidity and precursor numbers. These results demonstrate that the nature of primary TCD8+ responses to influenza A virus is highly influenced by Ag dose, which, in turn, determines the relative importance of Ag presentation, TCD8+ avidity, and precursor numbers in shaping the ID hierarchy. These findings provide valuable insights for future TCD8+-based vaccination strategies.<\/jats:p>","DOI":"10.4049\/jimmunol.1200089","type":"journal-article","created":{"date-parts":[[2012,12,12]],"date-time":"2012-12-12T02:43:07Z","timestamp":1355280187000},"page":"36-47","source":"Crossref","is-referenced-by-count":21,"title":["Increasing Viral Dose Causes a Reversal in CD8+ T Cell Immunodominance during Primary Influenza Infection due to Differences in Antigen Presentation, T Cell Avidity, and Precursor Numbers"],"prefix":"10.1093","volume":"190","author":[{"given":"Fabio","family":"Luciani","sequence":"first","affiliation":[{"name":"Infection and Inflammation Research Centre, School of Medical Sciences, University of New South Wales , Sydney, New South Wales 2052,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan T","family":"Sanders","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences, Austin Hospital , Heidelberg, Victoria 3084,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Oveissi","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences, Austin Hospital , Heidelberg, Victoria 3084,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken C","family":"Pang","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences, Austin Hospital , Heidelberg, Victoria 3084,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weisan","family":"Chen","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences, Austin Hospital , Heidelberg, Victoria 3084,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,1,1]]},"reference":[{"key":"2025032406185722100_r1","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.immuni.2006.09.005","article-title":"Confronting complexity: real-world immunodominance in antiviral CD8+ T cell responses","volume":"25","author":"Yewdell","year":"2006","journal-title":"Immunity"},{"key":"2025032406185722100_r2","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1084\/jem.193.11.1319","article-title":"Immunoproteasomes shape immunodominance hierarchies of antiviral CD8(+) T cells at the levels of T cell repertoire and presentation of viral antigens","volume":"193","author":"Chen","year":"2001","journal-title":"J. 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