The disruption of CD28B7 interactions impairs various effector functions elicited byiNKT cells. the responsiveness ofiNKT cells to disease-tailored glycolipids and select costimulatory ligands. == NKT cells: a brief overview == == Definition, subsets and localization == NKT cells constitute a numerically minor but functionally prominent subpopulation of lymphocytes that were initially defined based on their simultaneous expression of NK cell markers (e.g. mouse NK1.1 or DX5 and human CD161) and TCRs [1,2]. Although this definition still holds true for the vast majority of NKT cells, it is no longer considered precise because certain conventional T cell populations such as CD8+T cells can also express NK cell markers upon activation [3]. In addition, the expression level of NK cell markers by NKT cells varies in accordance to their maturation and activation states [4]. NKT cells are now defined based on the unique restriction of their TCRs by CD1d, a nonpolymorphic major histocompatibility complex (MHC) class I-like glycoprotein that presents glycolipid molecules to NKT cells. Similar to their conventional counterparts, NKT cells develop in the thymus and express an TCR [2]. However, unlike conventional T cells that are positively selected by cortical thymic epithelial cells and recognize peptide:MHC Silibinin (Silybin) complexes, the positive selection of NKT cells depends on CD4+CD8+thymocytes that express CD1d. The identity of endogenous CD1d-restricted glycolipid antigens participating in the positive selection of NKT cells and possibly contributing to the maintenance of their partially activated phenotype remains elusive. Furthermore, whether cells of the NKT lineage undergo negative selection in the thymus to eliminate autoaggressive cells has yet to be established. CD1d restriction is the cornerstone of NKT cell development and responsiveness. The advent of CD1d tetramer reagents loaded with NKT cell glycolipid ligands has allowed the accurate detection, enumeration and functional characterization of these cells [5,6]. Most CD1d-restricted NKT cells express an invariant TCR chain exhibiting the characteristic V14-J18 and V24-J18 gene rearrangements in mice and humans, Mouse monoclonal to CARM1 respectively [1]. This chain pairs with a limited set of TCR chains (V8.2, V2 or V7 in mice and V11 in humans), thereby defining type I or invariant NKT (iNKT) cells.iNKT cells recognize and respond to the marine sponge-derived glycolipid -GalCer. A smaller and relatively poorly studied subset of CD1d-restricted NKT cells, which are known as type II or variant NKT (vNKT) cells, express a diverse TCR repertoire and fail to recognize Silibinin (Silybin) -GalCer [2]. In this review, we focus oniNKT cells and their potential for immunotherapy. MouseiNKT cells are categorized into CD4+CD8and CD4CD8double negative (DN) subsets. An additional CD4CD8+subset exists in humans [7].iNKT cells occur in low abundance in blood and in various tissues including the thymus, bone marrow, spleen and lymph nodes. Exceptions include the mouse liver and human omentum, which house unusually large numbers ofiNKT cells [8]. Importantly,iNKT cell subsets found in different locations are functionally heterogeneous [7,912]. == Means and modes of activation == The canonical TCR ofiNKT cells (iTCR) recognizes glycolipid antigens in the context of CD1d, which is expressed by a variety of cell types including professional antigen-presenting cells (pAPCs). Certain microbial glycolipids such as those derived fromNovosphingobium(formerlySphingomonas) spp.,Ehrlichiaspp. andBorrelia burgdorferiinduceiNKT cell activation in a TCR-dependent fashion [13]. However, -GalCer is the most widely studied ligand for mouse and humaniNKT cells. Initially found in an extract ofAgelas mauritanius, -GalCer might have originated from microorganisms symbiotic with this marine sponge [14]. Although -GalCer is not a natural mammalian product, it has been employed extensively as an experimental tool to studyiNKT cells and has also been used in clinical trials. Almost alliNKT cell antigens have a lipid tail that is buried deep within the hydrophobic pocket of CD1d as well as a sugar head that protrudes out of CD1d and is accessed by theiTCR chain [15]. Unlike conventional TCRs, whose and chains are both involved in cognate peptide recognition near the centre of the MHC platform,iTCR is rotated clockwise and pushed laterally, thereby allowing only the chain to make contact with the galactose ring of -GalCer; the chain helps stabilize theiTCRCD1d interaction [15]. The relative diversity of theiTCR chain allowsiNKT cells to detect distinct structural Silibinin (Silybin) features of various CD1d-restricted glycolipid antigens [16]. The length of both acyl and phytosphingosine chains of -GalCer analogs controls the stability of CD1d binding [17]; however, the binding affinity of theiTCR for -Gal-Cer:CD1d complexes is influenced by the distance from the phytosphingosine string [17]. This may at least partly explain the distinctive cytokine replies elicited byiNKT cells activated with glycolipid antigens filled with the same glucose mind but different lipid tails. iNKT cells could be activated by bacteria lackingiTCR ligands Silibinin (Silybin) [18] also. This indirect activation setting is normally mediated by dendritic cells (DCs) secreting.