Abstract
Natural killer T (NKT) cells comprise a family of specialized T cells that recognize lipid antigens presented by CD1d. Based on their T cell receptor (TCR) usage and antigen specificities, CD1d-restricted NKT cells have been divided into two main subsets: type I NKT cells that use a canonical invariant TCR α-chain and recognize α-galactosylceramide (α-GalCer), and type II NKT cells that use a more diverse αβ TCR repertoire and do not recognize α-GalCer. In addition, α-GalCer-reactive NKT cells that use non-canonical αβ TCRs and CD1d-restricted T cells that use γδ or δ/αβ TCRs have recently been identified, revealing further diversity among CD1d-restricted T cells. Importantly, in addition to their distinct antigen specificities, functional differences are beginning to emerge between the different members of the CD1d-restricted T cell family. In this review, while using type I NKT cells as comparison, we will focus on type II NKT cells and the other non-invariant CD1d-restricted T cell subsets, and discuss our current understanding of the antigens they recognize, the formation of stimulatory CD1d/antigen complexes, the modes of TCR-mediated antigen recognition, and the mechanisms and consequences of their activation that underlie their function in antimicrobial responses, anti-tumor immunity, and autoimmunity.
Highlights
The immune system has been separated into innate and adaptive immunity
Based on the ability of human CD1b molecules to present lipid antigens from Mycobacterium tuberculosis (Mtb) to diverse CD1b-restricted T cells [7] and due to the similarities between CD1b and CD1d intracellular trafficking and localization in humans [95], we investigated Mtb lipids for antigens that may be recognized by type II natural killer T (NKT) cells
The first indication that type II NKT cells can contribute to protective immunity during viral infection came from studies in mice using diabetogenic encephalomyocarditis virus-induced pathology (EMCV-D) that is characterized by hind-limb paralysis and impaired glucose-tolerance resulting from virus cytopatic effects on neuronal cells and islet cells, respectively
Summary
The immune system has been separated into innate and adaptive immunity. In an unconventional way, innate T cells such as CD1d-restricted natural killer T (NKT) cells, MR1restricted mucosal-associated invariant T (MAIT) cells, γδ T cells, and some CD1a, b, c-restricted T cells share features of both innate and adaptive immune cells, allowing them to form a critical bridge between the two arms of the immune system [1,2,3,4]. NKT cells recognize lipid antigens presented by the monomorphic MHC class-I-like molecule CD1d and are highly conserved in humans and mice. In response to a wide range of self- and foreign antigens, NKT cells are activated rapidly and exhibit both pro-inflammatory and immunoregulatory characteristics, resulting in either protective or harmful roles in numerous pathological states in mice and humans, including microbial infection, autoimmune disease, allergic disease, and cancer [5,6,7,8,9,10]. Type I (or invariant) NKT cells constitute the first and best characterized subset, and use an invariant
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