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In addition, many reports have identified reduced primary CD8+ T cell responses in the absence of CD4+ T cell help, which often coincides with reduced Ag or pathogen clearance. In this study, we demonstrate that absence of CD4+ T cells at the time of adenovirus vector immunization of mice led to immediate impairments in early CD8+ T cell functionality and differentiation. Unhelped CD8+ T cells exhibited a reduced effector phenotype, decreased ex vivo cytotoxicity, and decreased capacity to produce cytokines. This dysfunctional state was imprinted within 3 d of immunization. Unhelped CD8+ T cells expressed elevated levels of inhibitory receptors and exhibited transcriptomic exhaustion and anergy profiles by gene set enrichment analysis. Dysfunctional, impaired effector differentiation also occurred following immunization of CD4+ T cell\u2013deficient mice with a poxvirus vector. This study demonstrates that following priming with viral vectors, CD4+ T cell help is required to promote both the expansion and acquisition of effector functions by CD8+ T cells, which is accomplished by preventing immediate dysfunction.<\/jats:p>","DOI":"10.4049\/jimmunol.1600591","type":"journal-article","created":{"date-parts":[[2016,7,23]],"date-time":"2016-07-23T02:59:27Z","timestamp":1469242767000},"page":"1809-1822","source":"Crossref","is-referenced-by-count":58,"title":["Immediate Dysfunction of Vaccine-Elicited CD8+ T Cells Primed in the Absence of CD4+ T Cells"],"prefix":"10.1093","volume":"197","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9694-2216","authenticated-orcid":false,"given":"Nicholas M","family":"Provine","sequence":"first","affiliation":[{"name":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9995-1804","authenticated-orcid":false,"given":"Rafael A","family":"Larocca","sequence":"additional","affiliation":[{"name":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4498-7893","authenticated-orcid":false,"given":"Malika","family":"Aid","sequence":"additional","affiliation":[{"name":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Penaloza-MacMaster","sequence":"additional","affiliation":[{"name":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4318-7624","authenticated-orcid":false,"given":"Alexander","family":"Badamchi-Zadeh","sequence":"additional","affiliation":[{"name":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica N","family":"Borducchi","sequence":"additional","affiliation":[{"name":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen B","family":"Yates","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology, Dana-Farber Cancer Institute , Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Abbink","sequence":"additional","affiliation":[{"name":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marinela","family":"Kirilova","sequence":"additional","affiliation":[{"name":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4452-5445","authenticated-orcid":false,"given":"David","family":"Ng\u2019ang\u2019a","sequence":"additional","affiliation":[{"name":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Bramson","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, McMaster University , Hamilton, Ontario L8S 4K1,","place":["Canada"]},{"name":"Michael G. DeGroote Institute for Infectious Disease Research, McMaster University , Hamilton, Ontario L8S 4K1,","place":["Canada"]},{"name":"McMaster Immunology Research Centre, McMaster University , Hamilton, Ontario L8S 4K1,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W Nicholas","family":"Haining","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology, Dana-Farber Cancer Institute , Boston, MA 02215"},{"name":"Broad Institute of MIT and Harvard , Cambridge, MA 02142"},{"name":"Division of Hematology\/Oncology, Children\u2019s Hospital, Harvard Medical School , Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan H","family":"Barouch","sequence":"additional","affiliation":[{"name":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA 02215"},{"name":"Ragon Institute of MGH, MIT, and Harvard , Boston, MA 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,9,1]]},"reference":[{"key":"2025030617480465400_r1","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/nri.2015.10","article-title":"The multifaceted role of CD4+ T cells in CD8+ T cell memory","volume":"16","author":"Laidlaw","year":"2016","journal-title":"Nat. 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