Intradermal NKT cell activation during DNA priming in heterologous prime‐boost vaccination enhances T cell responses and protection against Leishmania

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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 α‐galactosyl‐ceramide (αGalCer) during intradermal DNAp36 priming was examined. Vaccinated mice receiving αGalCer + 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 αGalCer + DNAp36 priming resulted in higher numbers of antigen‐reactive effector CD4+ and CD8+ T cells producing granzyme and IFN‐γ, 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 αGalCer. Notably 5 months after boosting, mice vaccinated with DNAp36 + αGalCer continued to show sustained and heightened T cell immune responses. Thus, heterologous prime‐boost vaccination using αGalCer 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).