TheIn VivoResponse of Invariant Natural Killer T Cells to Glycolipid Antigens

Abstract

Invariant natural killer T (iNKT) cells are a subset of T lymphocytes that recognizes glycolipid antigens presented by the major histocompatibility complex class I-related protein CD1d. Although iNKT cells have received a lot of attention as targets for the development of immunotherapies, few studies have investigated the in vivo response of iNKT cells to glycolipid antigen activation. Accumulating evidence indicates that iNKT cells generate a dynamic response to in vivo activation by glycolipid antigens that is characterized by surface receptor downmodulation, expansion, cytokine production, cross talk with other cells, homeostatic contraction, and acquisition of an anergic phenotype. These studies provide new insight into the biology of iNKT cells and have important implications for designing safe and effective iNKT cell-based vaccines and therapies.

Impact of bacteria on the phenotype, functions, and therapeutic activities of invariant NKT cells in mice

“…iNKT cell hyporesponsiveness induced by bacteria exhibited a number of similarities to iNKT cell anergy induced by α-GalCer (15). First, as already discussed, iNKT cell hyporesponsiveness correlated with sustained NK1.1 downregulation by splenic iNKT cells ( Figure 1B), and we observed a similar downregulation of the activating NK cell receptor NKG2D and the CD94 subunit of the NKG2/CD94 family of NK cell receptors (Supplemental Figure 3).…”

“…In sharp contrast, little is known regarding the immune response mediated by glycolipid-reactive, CD1d-restricted iNKT cells. We and others have shown that treatment of mice with the potent iNKT cell agonist α-GalCer results in the rapid activation and proliferation of these cells, followed by homeostatic contraction of the iNKT cell population and acquisition of an anergic phenotype (15). Here we have demonstrated that iNKT cells activated in response to multiple bacterial microorganisms acquire a similar hyporesponsive phenotype, which can significantly impact subsequent iNKT cell-mediated immune responses and the efficacy of iNKT cell-based immunotherapy.…”

“…α-GalCer potently activates iNKT cells to secrete a mixture of Th1 and Th2 cytokines. iNKT cells activated in this manner transactivate a variety of other cell types, including APCs, NK cells, and conventional T and B cells (15). The potent immunostimulatory activities of α-GalCer on APCs, in particular DCs, have been exploited for the development of vaccine adjuvants.…”

Glycolipid ligands of invariant natural killer T cells as vaccine adjuvants

“…The cytokines secreted by activated iNKT cells amplify the immune response initiated by these cells through transactivation of other cell types, including DCs, macrophages, NK cells, B cells and conventional CD4 and CD8 T cells [75–79]. This is evidenced by rapid upregulation of the activation marker CD69 or NK and B and T cells, and by induction of various costimulatory molecules on DCs, macrophages and B cells, following in vivo injection of α-GalCer.…”

Natural killer T cells in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis

“…15 Following TCR engagement, iNKT cells rapidly produce a variety of cytokines and exhibit cytotoxic activity. 16,17 One unusual property of iNKT cells is their capacity to produce mixtures of cytokines typically associated with either pro-inflammatory [e.g. interferon-c (IFN-c) 19 and several subsets of regulatory iNKT cells.…”