title: Heterologous vaccination against human tuberculosis modulates antigen-specific CD4+ T-cell function.
abstract: Heterologous prime-boost strategies hold promise for vaccination against tuberculosis. However, the T-cell characteristics required for protection are not known. We proposed that boost vaccines should induce long-lived functional and phenotypic changes to T cells primed by Bacille Calmette Guerin (BCG) and/or natural exposure to mycobacteria. We characterized changes among specific CD4(+) T cells after vaccination with the MVA85A vaccine in adults, adolescents, and children. CD4(+) T cells identified with Ag85A peptide-bearing HLA class II tetramers were characterized by flow cytometry. We also measured proliferative potential and cytokine expression of Ag85A-specific CD4(+) T cells. During the effector phase, MVA85A-induced specific CD4(+) T cells coexpressed IFN-γ and IL-2, skin homing integrins, and the activation marker CD38. This was followed by contraction and a transition to predominantly IL-2-expressing, CD45RA(-) CCR7(+) CD27(+) or CD45RA(+) CCR7(+) CD27(+) specific CD4(+) T cells. These surface phenotypes were similar to Ag85A-specific T cells prior to MVA85A. However, functional differences were observed postvaccination: specific proliferative capacity was markedly higher after 6-12 months than before vaccination. Our data suggest that MVA85A vaccination may modulate Ag85A-specific CD4(+) T-cell function, resulting in greater recall potential. Importantly, surface phenotypes commonly used as proxies for memory T-cell function did not associate with functional effects of vaccination.
authors.affiliation: South African Tuberculosis Vaccine Initiative and School of Child and Adolescent Health, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: One B
authors.initials: OB
authors.lastname: Dintwe
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Day
authors.forename: Erica
authors.initials: E
authors.lastname: Smit
authors.forename: Elisa
authors.initials: E
authors.lastname: Nemes
authors.forename: Clive
authors.initials: C
authors.lastname: Gray
authors.forename: Michele
authors.initials: M
authors.lastname: Tameris
authors.forename: Helen
authors.initials: H
authors.lastname: McShane
authors.forename: Hassan
authors.initials: H
authors.lastname: Mahomed
authors.forename: Willem A
authors.initials: WA
authors.lastname: Hanekom
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Scriba
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis; D000217:Acyltransferases / Q000276:immunology*; D000293:Adolescent; D000328:Adult; D000942:Antigens, Bacterial / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology; D054400:Receptors, CCR7 / Q000378:metabolism; D014376:Tuberculosis / Q000276:immunology / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000276:immunology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism; D019444:Vaccines, DNA; D014765:Viral Vaccines / Q000276:immunology*; D055815:Young Adult
chemical_list: D000942:Antigens, Bacterial; C515370:CCR7 protein, human; D007376:Interleukin-2; C549320:MVA 85A; D054400:Receptors, CCR7; D032581:Tuberculosis Vaccines; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D019444:Vaccines, DNA; D014765:Viral Vaccines; D007371:Interferon-gamma; D000217:Acyltransferases; C112580:antigen 85A, Mycobacterium tuberculosis; D017493:Leukocyte Common Antigens; D051997:ADP-ribosyl Cyclase 1
keywords: HLA class II tetramer; MVA85A; Proliferation; T cells; Vaccine