title: Immediate Dysfunction of Vaccine-Elicited CD8+ T Cells Primed in the Absence of CD4+ T Cells.
abstract: CD4(+) T cell help is critical for optimal CD8(+) T cell memory differentiation and maintenance in many experimental systems. 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-deficient 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.
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Nicholas M
authors.identifier: 0000-0002-9694-2216
authors.initials: NM
authors.lastname: Provine
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Rafael A
authors.identifier: 0000-0002-9995-1804
authors.initials: RA
authors.lastname: Larocca
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Malika
authors.identifier: 0000-0002-4498-7893
authors.initials: M
authors.lastname: Aid
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Pablo
authors.initials: P
authors.lastname: Penaloza-MacMaster
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Alexander
authors.identifier: 0000-0002-4318-7624
authors.initials: A
authors.lastname: Badamchi-Zadeh
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Erica N
authors.initials: EN
authors.lastname: Borducchi
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: Kathleen B
authors.initials: KB
authors.lastname: Yates
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Peter
authors.initials: P
authors.lastname: Abbink
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Marinela
authors.initials: M
authors.lastname: Kirilova
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: David
authors.identifier: 0000-0002-4452-5445
authors.initials: D
authors.lastname: Ng'ang'a
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4K1, Canada; Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada; McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario L8S 4K1, Canada;
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bramson
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215; Broad Institute of MIT and Harvard, Cambridge, MA 02142; Division of Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston, MA 02115; and.
authors.forename: W Nicholas
authors.initials: WN
authors.lastname: Haining
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; Ragon Institute of MGH, MIT, and Harvard, Boston, MA 02139 dbarouch@bidmc.harvard.edu.
authors.forename: Dan H
authors.initials: DH
authors.lastname: Barouch
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D016207:Cytokines / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005260:Female; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D007114:Immunization; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D014612:Vaccines / Q000276:immunology*
chemical_list: D016207:Cytokines; D014612:Vaccines