Abstract
NKT cells are an unusual population of T cells recognizing lipids presented by CD1d, a non-classical class-I-like molecule, rather than peptides presented by conventional MHC molecules. Type I NKT cells use a semi-invariant T cell receptor and almost all recognize a common prototype lipid, α-galactosylceramide (α-GalCer). Type II NKT cells are any lipid-specific CD1d-restricted T cells that use other receptors and generally don’t recognize α-GalCer. They play important regulatory roles in immunity, including tumor immunity. In contrast to type I NKT cells that most have found to promote antitumor immunity, type II NKT cells suppress tumor immunity and the two subsets cross-regulate each other, forming an immunoregulatory axis. They also can promote other regulatory cells including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and can induce MDSCs to secrete TGF-β, one of the most immunosuppressive cytokines known. In some tumors, both Tregs and type II NKT cells can suppress immunosurveillance, and the balance between these is determined by a type I NKT cell. We have also seen that regulation of tumor immunity can depend on the tissue microenvironment, so the same tumor in the same animal in different tissues may be regulated by different cells, such as type II NKT cells in the lung vs Tregs in the skin. Also, the effector T cells that protect those sites when Tregs are removed do not always act between tissues even in the same animal. Thus, metastases may require different immunotherapy from primary tumors. Newly improved sulfatide-CD1d tetramers are starting to allow better characterization of the elusive type II NKT cells to better understand their function and control it to overcome immunosuppression.
Highlights
NKT cells are a small population of true T cells which are distinct from conventional T cells in that their receptor recognizes lipids rather than peptides and is restricted by a non-classical class I-like molecule CD1d [1,2,3,4,5,6,7,8]
This study found that NKT cells were critical for protection in models of immunosurveillance dependent on exogenous production of IL-12, whereas others were more dependent on NK cells
The detailed mechanism of conversion of myeloid-derived suppressor cells (MDSCs) into stimulatory APCs is not clear, the effect of type I NKT cells on interacting MDSCs to induce maturation of the cells to become more stimulating myeloid cells is similar to what has been reported of interaction of type I NKT cells with α-GalCer-presenting immature Dendritic cells (DCs), which are induced to mature through CD40–CD40L interaction [114]
Summary
NKT cells are a small population of true T cells which are distinct from conventional T cells in that their receptor recognizes lipids rather than peptides and is restricted by a non-classical class I-like (class Ib) molecule CD1d [1,2,3,4,5,6,7,8]. When the Cardell et al, first identified CD1d-restricted T cells that lacked this semi-invariant TCR as residual CD4+ T cells present in MHC class II-deficient mice [18, 19], these were called non-classical or type II NKT cells and those with the semi-invariant TCR became known as classical or type I NKT cells, or iNKT cells for invariant NKT cells [2] Another key discovery was that virtually all type I NKT cells responded to a common prototype lipid, α-galactosylceramide (α-GalCer), originally isolated from a marine sponge but probably derived from microbes symbiotic with the sponge [20] (Table 1). Production and use of sulfatide tetramers has not been as straightforward
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