Glycolipid ligands of invariant natural killer T cells as vaccine adjuvants

Abstract

Invariant natural killer T (iNKT) cells are a unique subset of T lymphocytes that recognize glycolipid antigens in the context of the antigen-presenting molecule CD1d. Upon glycolipid antigen stimulation, iNKT cells rapidly produce copious amounts of immunomodulatory cytokines, leading to potent activation of a variety of innate and adaptive immune cells. These immune-potentiating properties of iNKT cells hold great promise for the development of vaccine adjuvants. This review aims to summarize the immunomodulatory activities of iNKT cell ligands and to discuss prospects for developing iNKT cell-based vaccine adjuvants.

Figure 1. iNKT cells and immunomodulatory glycolipids with adjuvant activity

(A) iNKT cells recognize glycolipids presented by CD1d. (B) α-GalCer and related glycolipids with promising adjuvant activities. DC: Dendritic cell; GalCer: Galactosylceramide; iNKT: Invariant natural killer T cell; TCR: T-cell receptor; ThrCer: Threitolceramide.

Figure 2. Enhancement of humoral and cellular immunity by iNKT cells

Upon coadministration of α-GalCer and a vaccine antigen, α-GalCer is presented by dendritic cells (DCs) and B cells to iNKT cells, resulting in upregulation of CD40 on these cells. DCs also upregulate other costimulatory molecules, including CD80, CD86 and CD70, and start producing cytokines, such as IL-12 and TNF-α. Activation of iNKT cells also results in the transactivation of NK cells, which start producing IFN-γ. The adjuvant activities of α-GalCer for adaptive cellular immune responses require presentation of α-GalCer and MHC class I- or class II-restricted antigens by the same DCs. The adjuvant activities of α-GalCer for adaptive humoral immunity are mediated indirectly through the adjuvant activities of α-GalCer on Th cell responses, and directly by interactions between antigen-specific B cells and iNKT cells. CTL: Cytotoxic T lymphocyte; GalCer: Galactosylceramide; iNKT: Invariant natural killer T cells; NK: Natural killer cell; TCR: T-cell receptor.

Figure 3. α-GalCer-loaded tumor cells as therapeutic tumor vaccines

In this promising vaccine strategy, tumor cells expressing CD1d (endogenously or following transfection with the CD1d gene) are loaded ex vivo with α-GalCer and then administered to tumor-carrying subjects. The tumor cells are then taken up by dendritic cells (DCs), which cross-present α-GalCer to iNKT cells, and tumor antigens to MHC-I- and -II-restricted T cells. The adjuvant activity of α-GalCer in this model is mediated through activation of tumor antigen-presenting DCs, with a key role for CD40–CD40L interactions between DCs and iNKT cells. CTL: Cytotoxic T lymphocytes; GalCer: Galactosylceramide; iNKT: Invariant natural killer T cells; TCR: T-cell receptor.