Abstract
The magnitude and durability of a plasmid DNA vaccine-induced immune response is shaped by immune effector molecules at the site of vaccination. In the present study, we show that antigen expression is modified by type II NKT cells, after interaction with a beta2-microglobulin-independent CD1d receptor. After activation, during the first days following plasmid DNA vaccination, NKT cells release IL-5 and MCP-1, leading to a T helper 0 (T(H)0) cytokine/chemokine profile and a stronger CD8(+)/CD4(+) T cell immune response. Our data indicate that this phenomenon was induced through the strong T(H)1 chemokine MCP-1 during the early phases of plasmid DNA vaccination because injecting the type II NKT cell-associated MCP-1 during the first 5 days led to 2-3-fold increases in vaccine-elicited T cell responses. This study demonstrates a critical role for NKT cells in plasmid DNA vaccine-induced immune responses. Manipulation of NKT cell function or co-administration of MCP-1 may represent novel methods for enhancing immune responses to plasmid DNA vaccines.
Highlights
Natural Killer (NK) and Natural Killer T (NKT) cells have distinct and complementary functions
The present study shows that type II NKT cells contribute to plasmid DNA antigen clearance and to changes in vaccine-induced cellular immune responses
Our findings increase the range of biologic functions mediated by type II NKT cells found so far: (i) In ulcerative colitis, type II NKT cells are present in the lamina propria of the colon, and lyse intestinal epithelial cells (38), suggesting that they may play the role of effector cells in the pathogenesis of ulcerative colitis (39); (ii) in a transgenic mouse model of acute hepatitis B infection, type II NKT cells have been shown to cause liver cell injury (40); (iii) type II NKT cells have been shown to regulate autoimmune diabetes in a TCR-transgenic mouse (41), (iv) they down-regulate tumor-immune surveillance in mouse models of cancer by enhancing TGF- production (12, 42), and (v) may contribute to the pathogenesis of allergic asthma (43)
Summary
6-Lystbg) (23–25) were purchased from the Jackson Laboratory. J␣18 KO mice (iNKT KO), mice missing the V␣14-J␣18 NKT cells, were a gift from Dr Mark E. Ceramides were injected via the intraperitoneal (intraperitoneal) route 3 days prior to plasmid DNA inoculations at a dose of 10 g in 200 l of sterile PBS, a dose at which the D-glucosyl-1-1Ј ceramide (C12) has been shown to totally deplete NKT function (29). CD8ϩ T lymphocytes from control mice immunized with untagged plasmid DNA-Luc exhibited Յ0.1% tetramer staining. We observed a total loss of Luc-specific T cell immune responses after NK/NK T cell depletion (Fig. 1D) These findings suggested that NK or NKT cells are important for eliciting strong DNA. DNA Vaccine Antigen Expression Damping Is Dependent on NKT Cells—In light of the evidence that NK and/or NKT cells influence adaptive immune responses and antigen clearance in plasmid DNAvaccinated mice, we designed experiments to define the contribu-
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