Non-classical Natural Killer T Cells Modulate Plasmid DNA Vaccine Antigen Expression and Vaccine-elicited Immune Responses by MCP-1 Secretion after Interaction with a β2-Microglobulin-independent CD1d

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 ␤2-microglobulin-independent Plasmid DNA vaccine-induced T cell memory responses are potentiated by innate immune responses that are generated during the first days after vaccination (1). At that time Natural Killer (NK) 2 and Natural Killer T (NKT) cells are attracted to the site of vaccine administration (2). Investigation into the function of both cell types following vaccination is important because in diverse biologic settings the release of NK or NKT cell-associated cytokines and chemokines has been shown to modulate adaptive T cell and humoral immune responses. Responding quickly, these cells have the capacity to produce cytokines and chemokines that help B cells produce antibodies, induce macrophages to develop enhanced microbicidal activity, and recruit T cells, neutrophils, eosinophils, and basophils to sites of infection and inflammation (3-9).NK and NKT cells have distinct and complementary functions. NK cells can recognize and eliminate tumors and virusinfected cells (3-5). NKT cells participate in immune processes associated with self-tolerance, including tumor rejection (10, 11), suppression of anti-tumor responses (12), down-regulation of autoimmune inflammatory diseases (13), immune privilege (14), tolerance to allografts and xenografts (15-17), fetal-maternal tolerance (18), protection against graft-versus-host disease (19), and protection against pathogens such as Cryptococcus (20) and hepatitis B virus (21).NK and NKT cells recognize target cells using distinct receptors. NK cell effector function is regulated by a balance between opposing signals delivered by inhibitory and activating receptors. A number of surface molecules expressed by NK cells, including CD2, CD16, CD69, and DNAM-1 have been implicated in the triggering of NK cell-mediated cytotoxicity. Additionally, the activating counterparts of the MHC-specific receptor p50 and the CD94/NKG2C molecules trigger NK-mediated cytotoxicity against MHC class I-expressing target cells. MHC class I negative targets are lysed after recognition by the cytotoxicity receptors NKp46, NKp44,.The majority of NKT cells express the NK lineage-specific receptor NK1.1 (CD161) and secrete cytokines upon recognition of CD1d. CD1d can present lipids and glycolipids as well as peptides to NKT cells. Invariant NKT (iNKT) cells or type I NKT cells make use of a restricted TCR repertoire, using an invariant TCR V␣14-J␣281 rearrangement and a limited set of TCR V␤ segments, suggesting that they recognize a limited set of CD1d-associated ligands (8, 9). A second group of CD1d-reactive NKT cells, referred to as type II NKT cells, use a diverse TCR repertoire that allows them to recognize a diversity of ligands presented on CD1d (8).Because plasmid DNA antigen clearance has been shown to be ␤2m-independent (22),...

Regulatory T Cells Suppress Natural Killer Cells during Plasmid DNA Vaccination in Mice, Blunting the CD8+ T Cell Immune Response by the Cytokine TGFβ

“…Early innate responders at the site of inoculation include NKT and NK cells [28] . Cytokine release by NKT cells was found to be important to initiate a potent antibody and T cell immune response to plasmid DNA vaccines [28] , [40] , [41] . Tregs may suppress NKT immune action at the site of injection.…”

“…Forty-eight hours following plasmid DNA vaccination, NK and NKT cells migrate to the vaccine injection site [28] , and an early innate immune response is initiated, leading to an increase in efficacy of plasmid DNA vaccination [39] . However, only NKT cells seem to be involved in potentiating these CD8 + T cell immune responses [40] , [41] . NK cells although being early at the site of inoculation seem to have no effect on CD8 + T cell plasmid DNA immune responses [41] , [43] .…”

“…However, only NKT cells seem to be involved in potentiating these CD8 + T cell immune responses [40] , [41] . NK cells although being early at the site of inoculation seem to have no effect on CD8 + T cell plasmid DNA immune responses [41] , [43] . We, therefore, hypothesized that Tregs may suppress NK cell-mediated immune activation.…”

“…Additionally, after Treg depletion, NKT KO mice showed a more rapidly decline of CD8 + T cell immune response than was observed for wildtype mice. This diminished CD8 + T cell immune response might be the result of the lack of T H 1 immune support by MCP-1, a major chemokine early released by NKT cells after plasmid DNA inoculation and found to be important for the magnitude of the vaccine-elicited immune response [41] .…”