title: Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy.
abstract: T cells with high functional avidity can sense and respond to low levels of cognate Ag, a characteristic that is associated with more potent responses against tumors and many infections, including HIV. Although an important determinant of T cell efficacy, it has proven difficult to selectively induce T cells of high functional avidity through vaccination. Attempts to induce high-avidity T cells by low-dose in vivo vaccination failed because this strategy simply gave no response. Instead, selective induction of high-avidity T cells has required in vitro culturing of specific T cells with low Ag concentrations. In this study, we combined low vaccine Ag doses with a novel potent cationic liposomal adjuvant, cationic adjuvant formulation 09, consisting of dimethyldioctadecylammonium liposomes incorporating two immunomodulators (monomycolyl glycerol analog and polyinosinic-polycytidylic acid) that efficiently induces CD4 Th cells, as well as cross-primes CD8 CTL responses. We show that vaccination with low Ag dose selectively primes CD4 T cells of higher functional avidity, whereas CD8 T cell functional avidity was unrelated to vaccine dose in mice. Importantly, CD4 T cells of higher functional avidity induced by low-dose vaccinations showed higher cytokine release per cell and lower inhibitory receptor expression (PD-1, CTLA-4, and the apoptosis-inducing Fas death receptor) compared with their lower-avidity CD4 counterparts. Notably, increased functional CD4 T cell avidity improved antiviral efficacy of CD8 T cells. These data suggest that potent adjuvants, such as cationic adjuvant formulation 09, render low-dose vaccination a feasible and promising approach for generating high-avidity T cells through vaccination.
authors.affiliation: Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; rob@ssi.dk berzofsj@mail.nih.gov.|Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen S, DK-2300, Denmark; and.
authors.forename: Rolf
authors.identifier: 0000-0003-4533-7304
authors.initials: R
authors.lastname: Billeskov
authors.affiliation: AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Corporation, Frederick, MD 21702.
authors.forename: Yichuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Shahram
authors.initials: S
authors.lastname: Solaymani-Mohammadi
authors.affiliation: Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Blake
authors.initials: B
authors.lastname: Frey
authors.affiliation: Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Shweta
authors.initials: S
authors.lastname: Kulkarni
authors.affiliation: Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen S, DK-2300, Denmark; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
authors.affiliation: Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen S, DK-2300, Denmark; and.
authors.forename: Else Marie
authors.initials: EM
authors.lastname: Agger
authors.affiliation: Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Yongjun
authors.identifier: 0000-0002-1568-4607
authors.initials: Y
authors.lastname: Sui
authors.affiliation: Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; rob@ssi.dk berzofsj@mail.nih.gov.
authors.forename: Jay A
authors.identifier: 0000-0002-0342-3194
authors.initials: JA
authors.lastname: Berzofsky
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006678:HIV / Q000276:immunology / Q000378:metabolism*; D015488:HIV Antigens / Q000276:immunology*; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050178:Monoglycerides / Q000737:chemistry; D011070:Poly I-C / Q000008:administration & dosage*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry
chemical_list: D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D016207:Cytokines; D015488:HIV Antigens; D008081:Liposomes; D050178:Monoglycerides; D000644:Quaternary Ammonium Compounds; C543328:monomycoloyl glycerol; C015831:dimethyldioctadecylammonium; D011070:Poly I-C