Turned on by danger: activation of CD1d‐restricted invariant natural killer T cells

Abstract

SummaryCD1d-restricted invariant natural killer T (iNKT) cells bear characteristics of innate and adaptive lymphocytes, which allow them to bridge the two halves of the immune response and play roles in many disease settings. Recent work has characterized precisely how their activation is initiated and regulated. Novel antigens from important pathogens have been identified, as has an abundant self-antigen, b-glucopyranosylcaramide, capable of mediating an iNKT-cell response. Studies of the iNKT T-cell receptor (TCR)-antigen-CD1d complex show how docking between CD1d-antigen and iNKT TCR is highly conserved, and how small sequence differences in the TCR establish intrinsic variation in iNKT TCR affinity. The sequence of the TCR CDR3b loop determines iNKT TCR affinity for ligand-CD1d, independent of ligand identity. CD1d ligands can promote T helper type 1 (Th1) or Th2 biased cytokine responses, depending on the composition of their lipid tails. Ligands loaded into CD1d on the cell surface promote Th2 responses, whereas ligands with long hydrophobic tails are loaded endosomally and promote Th1 responses. This information is informing the design of synthetic iNKT-cell antigens. The iNKT cells may be activated by exogenous antigen, or by a combination of dendritic cell-derived interleukin-12 and iNKT TCR-self-antigen-CD1d engagement. The iNKT-cell activation is further modulated by recent foreign or self-antigen encounter. Activation of dendritic cells through pattern recognition receptors alters their antigen presentation and cytokine production, strongly influencing iNKT-cell activation. In a range of bacterial infections, dendritic cell-dependent innate activation of iNKT cells through interleukin-12 is the dominant influence on their activity.

Recent advances in inflammatory bowel disease: mucosal immune cells in intestinal inflammation

“…An elegant mechanism involving natural killer T (NKT) cells, the epithelium and early life exposure to the microbiota, which could contribute to this ‘hygiene hypothesis’,18 has recently been reported by Blumberg and colleagues 19. Invariant NKT (iNKT) cells, expressing an invariant TCRα chain, are activated in response to endogenous and exogenous lipids presented by the non-polymorphic MHC class I-related molecule CD1d 20. CD1d-restricted iNKT cells produce IL-13, a cytokine associated with UC,21 and have been shown to be the main effectors of IL-13-dependent oxazolone colitis, a murine model that closely resembles UC 22.…”

Efficacy of ABX196, a new NKT agonist, in prophylactic human vaccination

“…A family of these glycolipids based on the α-galactosylceramide (α-GalCer) chemistry binds efficiently to CD1d molecules and stimulates specifically a small subset of regulatory lymphocytes called NKT cells. NKT cells are powerful adjuvants of immunity that are recruited rapidly at the site of injury (reviewed in [3]). The main mediators of that sequence of events are IFNγ and IL-4 that NKT cells secrete in large quantities upon activation; subsequent IL12 secretion from DCs, and upregulation of CD40/CD40L on NKT, DC, and B cells sustain the priming reaction.…”

Natural killer and natural killer T-like cells in splenectomised patients

“…Activation via CD1d initiates rapid production of a large number of both Th1 and Th2 immunoregulatory cytokines including IL-4, IL-10 and IFN-γ, activation of several immune cells (NK cells, T, B lymphocytes, dendritic cells) and increase in the cytolytic activity of NKT cells [38]. Due to the above abilities, NKT cells are called a "bridge" between innate and adaptive immunity [39]. Natural killer T cells are involved in a variety of immunological processes.…”