Natural killer T cells (NKT) are an innate-like population of T lymphocytes that recognize lipid antigens presented on the Major Histocompatibility Complex (MHC)-like molecule CD1d. Upon activation, NKT cells release an array of Th1 and Th2 cytokines that confers the ability to influence immune outcomes in a broad range of diseases, including cancer, tumor immunity, autoimmunity, allergy and infection. Thus, their immunomodulatory potential enables them to be of important therapeutic targets.
NKT cells are widely studied in mice and humans, and there are two main subsets, type I and type II. Type I NKT cells typically express an invariant α-chain (Vα14-Jα18 in mice, Vα24-Jα18 in humans) paired with a broad spectrum of β-chains (Vβ8.2, Vβ7 and Vβ2 in mice and Vβ11 in humans) and recognize α-Galactosylceramide (α-Galcer) and termed as ‘semi-invariant’ (iNKT) cells. Type II NKT cells express a diverse TCR repertoire and do not recognize α-Galcer. There also prevails a third repertoire of NKT cells in humans that do recognize α-Galcer presented by CD1d but express different TCRs from that of iNKT cells and termed as ‘Vα24- or non-canonical TCRs’. It is important to note, the prototypical NKT cell antigen, α-Galcer is now undergoing phase I/II clinical trials.
In our study, we have solved the crystal structure of a non-canonical NKT TCR-CD1d/α-Galcer complex, that revealed a ‘novel docking mode’ of TCR which is in clear contrast to type I and comparable with type II.Thus, our results shed light in understanding the basis of lipid antigen recognition and would also aid in modulating immune responses in various clinical settings.