Longitudinal requirement for CD4+ T cell help for adenovirus vector-elicited CD8+ T cell responses.
Despite the widespread use of replication-incompetent recombinant adenovirus (Ad) vectors as candidate vaccine platforms, the mechanism by which these vectors elicit CD8(+) T cell responses remains poorly understood. Our data demonstrate that induction and maintenance of CD8(+) T cell responses by Ad vector immunization is longitudinally dependent on CD4(+) T cell help for a prolonged period. Depletion of CD4(+) T cells in wild type mice within the first 8 d following Ad immunization resulted in dramatically reduced induction of Ag-specific CD8(+) T cells, decreased T-bet and eomesodermin expression, impaired KLRG1(+) effector differentiation, and atypical expression of the memory markers CD127, CD27, and CD62L. Moreover, these CD8(+) T cells failed to protect against a lethal recombinant Listeria monocytogenes challenge. Depletion of CD4(+) T cells between weeks 1 and 4 following immunization resulted in increased contraction of memory CD8(+) T cells. These data demonstrate a prolonged temporal requirement for CD4(+) T cell help for vaccine-elicited CD8(+) T cell responses in mice. These findings have important implications in the design of vaccines aimed at eliciting CD8(+) T cell responses and may provide insight into the impaired immunogenicity of vaccines in the context of AIDS and other CD4(+) T cell immune deficiencies.
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215; and.
Nicholas M
NM
Provine
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215; and.
Rafael A
RA
Larocca
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215; and.
Pablo
P
Penaloza-MacMaster
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215; and.
Erica N
EN
Borducchi
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215; and.
Anna
A
McNally
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215; and.
Lily R
LR
Parenteau
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215; and.
David R
DR
Kaufman
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215; and Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139 dbarouch@bidmc.harvard.edu.
Dan H
DH
Barouch
D000256:Adenoviridae; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D001428:Bacterial Vaccines / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout
D015703:Antigens, CD; D001428:Bacterial Vaccines