Invariant natural killer T cells as sensors and managers of inflammation

Abstract

Invariant natural killer T (iNKT) cells are a subset of innate-like lymphocytes that recognize glycolipid antigens bound by the major histocompatibility complex (MHC)-class-I-related protein CD1d. iNKT cells are activated early during a variety of infections and inflammatory diseases and contribute to the subsequent development of adaptive immune responses. Consequently, iNKT cells play a critical role in the development and resolution of inflammatory diseases and represent attractive targets for the development of immunotherapies. Recent studies have provided important insight into the mechanisms by which iNKT cells become activated in response to diverse inflammatory stimuli. These new findings should be instrumental to promote the immunomodulatory properties of iNKT cells for treatment of inflammatory diseases.

Figure 1

Mechanisms of invariant natural killer T (iNKT) cell activation during inflammation. (a) Direct activation of iNKT cells by interaction of the invariant T cell receptor (iTCR) with exogenous antigens presented by CD1d molecules on antigen-presenting cells (APCs). (b) Indirect activation of iNKT cells by cytokines such as interleukin (IL)-12 produced by APCs in response to agonists of pattern-recognition receptors (PRRs) in the presence (+) or absence (–) of weak interactions of the iTCR with self antigens. (c) Additional mechanisms that can contribute to iNKT cell activation during inflammation in certain situations: (i) signaling of the peroxisome proliferator activated receptor (PPAR)γ in response to lipid agonists might induce CD1d expression; (ii) superantigens such as staphylococcal enterotoxin B (SEB) might crosslink peptide–major histocompatibility complex (MHC) class II (pMHCII) complexes and certain TCR Vβ chains (Vβ8.2 in the case of SEB) on iNKT cells; (iii) antigen (Ag)–IgG complexes might activate FcγRIII on iNKT cells; (iv) NK cell receptors on iNKT cells might be engaged by their counter-receptors on APCs; (v) co-stimulatory receptors on iNKT cells might be engaged by their counter-receptors on APCs; (vi) T cell immunoglobulin-like mucin-like (TIM)-1 on iNKT cells might bind with phosphatidylserine on apoptotic cells; (vii) TCR-activated iNKT cells might induce expression of Toll-like receptors (TLRs) that can be engaged by their ligands; and (viii) neurotransmitters such as noradrenaline might interact with their receptors on iNKT cells. iNKT cells activated by these diverse signals may produce a variety of cytokines, as indicated.