title: Intradermal NKT cell activation during DNA priming in heterologous prime-boost vaccination enhances T cell responses and protection against Leishmania.
abstract: Heterologous prime-boost vaccination employing DNA-vaccinia virus (VACV) modality using the Leishmania homologue of receptors for activated C kinase (LACK) (p36) antigen has been shown to elicit protective immunity against both murine cutaneous and visceral leishmaniasis. However, DNA priming is known to have limited efficacy; therefore in the current study the effect of NKT cell activation using alpha-galactosyl-ceramide (alphaGalCer) during intradermal DNAp36 priming was examined. Vaccinated mice receiving alphaGalCer + DNAp36 followed by a boost with VVp36 appeared to be resolving their lesions and had at ten- to 20-fold higher reductions in parasite burdens. NKT cell activation during alphaGalCer + DNAp36 priming resulted in higher numbers of antigen-reactive effector CD4(+) and CD8(+) T cells producing granzyme and IFN-gamma, with lower levels of IL-10. Although immunodepletion studies indicate that both CD4 and CD8 T cells provide protection in the vaccinated mice, the contribution of CD4(+) T cells was significantly increased in mice primed with DNAp36 together with alphaGalCer. Notably 5 months after boosting, mice vaccinated with DNAp36 + alphaGalCer continued to show sustained and heightened T cell immune responses. Thus, heterologous prime-boost vaccination using alphaGalCer during priming is highly protective against murine cutaneous leishmaniasis, resulting in the heightened activation and development of CD4 and CD8 T cells (effector and memory T cells).
authors.affiliation: Department of Epidemiology & Public Health, Yale University School of Medicine, New Haven, CT 06520-8034, USA.
authors.forename: Blaise
authors.initials: B
authors.lastname: Dondji
authors.forename: Eszter
authors.initials: E
authors.lastname: Deak
authors.forename: Karen
authors.initials: K
authors.lastname: Goldsmith-Pestana
authors.forename: Eva
authors.initials: E
authors.lastname: Perez-Jimenez
authors.forename: Mariano
authors.initials: M
authors.lastname: Esteban
authors.forename: Sachiko
authors.initials: S
authors.lastname: Miyake
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamura
authors.forename: Diane
authors.initials: D
authors.lastname: McMahon-Pratt
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D005699:Galactosylceramides / Q000276:immunology; D005822:Genetic Vectors / Q000235:genetics; D053804:Granzymes / Q000378:metabolism; D007111:Immunity, Cellular / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D007896:Leishmaniasis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008213:Lymphocyte Activation / Q000276:immunology*; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000378:metabolism; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology; D012867:Skin / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014611:Vaccination / Q000379:methods; D019444:Vaccines, DNA / Q000276:immunology* / Q000627:therapeutic use; D014616:Vaccinia virus / Q000235:genetics
chemical_list: D000953:Antigens, Protozoan; D005699:Galactosylceramides; D015800:Protozoan Proteins; D019444:Vaccines, DNA; C493154:alpha-galactosylceramide; D016753:Interleukin-10; C093139:LACK antigen, Leishmania; D009569:Nitric Oxide; D007371:Interferon-gamma; D053804:Granzymes