Recently much attention has been devoted to the regulation of immune responses by invariant natural killer T (iNKT) cells. These iNKT cells comprise a subset of T cells that share αβ T cell receptor (TCR) and NK cell receptor structures with conventional T cells and NK cells. However, they are unique in that the majority of iNKT cells (also known as Type I NKT cells) express a semi-invariant Vα14Jα18 TCR chain paired preferentially with a Vβ8, Vβ2, or Vβ7 chain in mice and homologous Vα24-Jα18 and Vβ11 chains in humans. While most iNKT cells express the CD4 T cell co-receptor, other iNKT cells do not express CD4 or CD8. Type II and Type III NKT cells are “variant” as they express a diverse TCR repertoire. In contrast to conventional T cells that recognize antigenic peptides, iNKT cells are activated by glycolipid antigens presented by CD1d, a non-classical MHC class I like antigen-presenting molecule. iNKT cells are distinguished by their ability to secrete large amounts of cytokines (e.g. IFN-γ, IL-4, IL-13) upon activation. Whereas iNKT cells localize in significant numbers in the bone marrow, thymus, liver, spleen and peripheral blood, they are found at a much lower frequency in lymph nodes. This wide tissue distribution of iNKT cells as well as their ability to secrete both Th1- and Th2-type cytokines may enable them to mediate a vast array of innate and adaptive immune responses. Type II NKT cells are restricted by CD1d while type III NKT cells are CD1d-independent and are restricted by class I and II MHC molecules.
Although the mechanisms are not completely understood, activated iNKT cells can both protect against and exacerbate several types of adaptive immune responses including autoimmune disease, maintenance of self-tolerance, responses to tumors and microbial pathogens, and asthma. These variable immunoregulatory properties of iNKT cells may be attributable in part to the type, dose and route of administration of a given iNKT cell ligand, stage of activation and/or maturation of iNKT cells in a given tissue, as well as the tissue site of localization of iNKT cells and other regulatory or effector T cells and dendritic cells (DC) with which they interact. Importantly, activation of iNKT cells with the α-galactosylceramide (α-GalCer) superagonist glycosphingolipid can transactivate B cells, NK cells, conventional T cells and dendritic cells (DCs), indicating that α-GalCer can act as an adjuvant to promote many other antigen-specific responses during innate and adaptive immunity. Furthermore, crosstalk between DC and iNKT cells can shape an immune response and control the relative percentage of DC subsets in a cytokine- and chemokine-dependent manner. iNKT cells can also potently induce DC maturation. Recent findings also indicate that naturally occurring CD4+CD25+ regulatory T cells (Tregs) can cooperate with iNKT cells in transplantation, oral tolerance to nickel, cancer and prevention of autoimmune myasthenia and autoimmune type 1 diabetes. Thus, current evidence supports the notion that Treg-iNKT cell crosstalk occurs via an immunoregulatory network in which activated iNKT cells modulate Treg function by IL-2 dependent mechanisms, while Tregs can suppress the proliferation, cytokine release and cytotoxic activity of iNKT cells by cell-contact mechanisms.
Despite the fact that the synthetic α-GalCer ligand may not be a natural antigen for iNKT cells due to its α-anomeric linkage, recent reports demonstrate that human and mouse iNKT cells can recognize glycosphingolipids from non-pathogenic bacteria as well as antigens other than glycosphingolipids (e.g. glycoglycerol lipids) from pathogenic microbes. Accordingly, this unconventional type of antigen recognition by iNKT cells might be the driver for the selection of expression of invariant TCRs by iNKT cells during evolution. Inasmuch as the immunomodulatory activities of iNKT cells are inducible by this array of natural and synthetic glycolipid antigens, such reagents may prove valuable for the development of vaccine adjuvants and for immunotherapy of cancer, infections, autoimmune and inflammatory conditions, transplant rejection and allergic reactions. However, a potential caveat is that activation of iNKT cells by such agents may also elicit adverse side reactions such as liver toxicity, abortion, and atherogenesis. Therefore, as we go forward and attempt to design and develop safe and efficacious iNKT cell-based therapeutics, it is crucial that we establish a more complete understanding of the biology of iNKT cells during various types of immune responses in vivo.
This “from iNKT cell biology to therapy” roadmap constitutes the focus of the articles in this issue of International Reviews of Immunology. These articles will review the developmental biology of iNKT cells, cell biology of iNKT responsiveness to glycolipids in vivo, and roles that iNKT cells play in the regulation of various autoimmune diseases (type 1 diabetes, multiple sclerosis, systemic lupus erythmatosous, arthritis, and inflammatory bowel disease), peripheral tolerance during anterior chamber associated immune deviation in the eye, oral tolerance, asthma and airway hyperreactivity.
As Winston Churchill said in November, 1942, “Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning”. With respect to our understanding iNKT cell biology and development of iNKT cell based therapies, it may be appropriate to acknowledge that we have arrived at the end of the beginning.