Figure 3 of this Letter contains an inadvertently duplicated panel: the PBS 30 panel is identical to the aGalCer panel (top right). The corrected panels are shown here. Our results and conclusions are unaffected by this oversight. CORRIGENDUM
NKT cells represent a distinct lineage of T cells that coexpress a conserved alphabeta T cell receptor (TCR) and natural killer (NK) receptors. Although the TCR of NKT cells is characteristically autoreactive to CD1d, a lipid-presenting molecule, endogenous ligands for these cells have not been identified. We show that a lysosomal glycosphingolipid of previously unknown function, isoglobotrihexosylceramide (iGb3), is recognized both by mouse and human NKT cells. Impaired generation of lysosomal iGb3 in mice lacking beta-hexosaminidase b results in severe NKT cell deficiency, suggesting that this lipid also mediates development of NKT cells in the mouse. We suggest that expression of iGb3 in peripheral tissues may be involved in controlling NKT cell responses to infections and malignancy and in autoimmunity.
NKT cells express a conserved, semi-invariant αβ T cell receptor, which has specificity for a selfglycosphingolipids and microbial cell wall α-glycuronosylceramide antigens presented by CD1d molecules. Here we report the crystal structure of CD1d in complex with a short-chain synthetic variant of α-galalctosylceramide at 2.2 Å resolution. This structure elucidated the basis for the high specificity of these microbial ligands and explained the restriction of the α-linkage as a unique pathogen-specific pattern recognition motif. Comparison of the binding of altered lipid ligands to CD1d and TCR shows the differential T H 1-and T H 2-like properties of NKT cells may originate primarily from marked differences in their loading in different cell-types and, hence, in their tissue distribution in vivo.NKT cells are a conserved lymphocyte lineage expressing a semi-invariant TCR (V α 14-J α 18-V β 8, 7 or 2 in mouse and V α 24-J α 18-V β 11 in human . They are important in regulating a variety of microbial, allergic, autoimmune and tumor conditions through the rapid and substantial secretion of T H 1 and T H 2 cytokines and chemokines 1 . Unlike other T cells, NKT cells are restricted to a non-MHC molecule, CD1d, which binds lipids and glycolipids instead of peptides. Whereas other CD1 isotypes in humans can present a large variety of bacterial compounds that stimulate individual T cell clones expressing diverse TCRs 2 , CD1d appears to have specialized in the presentation of a limited set of lipids for recognition by the entire, or a large fraction of, NKT cell population. Two major classes of agonist ligands of mouse and human NKT cells have been uncovered, a self glycosphingolipid (GSL) isoglobotrihexosylceramide (iGb3) 3 , and a family of α-glycuronosylceramides that substitute for LPS in the cell wall of some Gram-negative LPS-negative bacteria including Sphingomonas 4-6 . Although iGb3 appears to be the only required ligand for NKT cell development, the dual specificity for self and foreign ligands, a general feature of many innatelike lymphocyte subsets 7 , underlies the recruitment and activation of NKT cells in various disease conditions, including microbial infections 5 . Another microbial ligand present in the *Corresponding authors: lteyton@scripps.edu, Phone: (858) 784-2728, Fax: (858) wilson@scripps.edu, Phone: (858) Fax: (858) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript cell wall of mycobacteria, phosphatidylinositol mannoside (PIM 4 ) also appears to be a natural ligand of NKT cells 8 .Microbial α-glycuronosylceramides are of particular interest because of their relevance in the context of infection in vivo and their very close structural homology with a highly potent agonist of human and murine NKT cells, α-galactosyl ceramide (α-GalCer) 9 , that was previously isolated from marine sponges. These molecules are both α-stereo isomers, a stereochemistry absent from mammalian glycosphingolipids, and phyto-ceramides due to the additional hydroxyl group at the C 4 posi...
It is now established that CD1 molecules present lipid antigens to T cells, although it is not clear how the exchange of lipids between membrane compartments and the CD1 binding groove is assisted. We report that mice deficient in prosaposin, the precursor to a family of endosomal lipid transfer proteins (LTP), exhibit specific defects in CD1d-mediated antigen presentation and lack Vα14 NKT cells. In vitro, saposins extracted monomeric lipids from membranes and from CD1, thereby promoting the loading as well as the editing of lipids on CD1. Transient complexes between CD1, lipid, and LTP suggested a "tug-of-war" model in which lipid exchange between CD1 and LTP is on the basis of their respective affinities for lipids. LTPs constitute a previously unknown link between lipid metabolism and immunity and are likely to exert a profound influence on the repertoire of self, tumor, and microbial lipid antigens.CD1 molecules have evolved a unique hydrophobic binding groove that binds lipid antigens in both the secretory and endosomal compartments for presentation to T lymphocytes (1). In mice, the main population of CD1-restricted T cells, called Vα14 NKT cells, express a † These authors contributed equally to this work. To whom correspondence should be addressed. abendela@bsd.uchicago.edu (A.B.); lteyton@scripps.edu (L.T.). * These authors contributed equally to this work. CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptsemi-invariant Vα14-Jα18/Vβ8 T cell receptor (TCR). These cells exhibit reactivity against CD1d in combination with endogenous ligands (2) that can be mimicked by α-galactosylceramide (αGC) (3). This population is conserved among mammalian species and regulates immune responses (4, 5). Like human CD1b-restricted T cells specific for mycobacterial glycolipids (6), Vα14 NKT cells are dependent on endosomal trafficking of CD1d for natural antigen recognition (7-10). Other endogenous or exogenous antigens do not require endosomal trafficking, however, suggesting that loading may be achieved in distinct cellular compartments depending on the nature of the antigen (9,11,12). CD1 endosomal trafficking is tightly controlled by cytoplasmic tail-encoded tyrosine-containing motifs binding adaptor protein 2 and 3 (AP-2 and AP-3) complexes, as well as by association with the invariant chain (Ii) or Ii/major histocompatibility (MHC) class II complexes (13-16).Because lipids are integral membrane components that might require lipid transfer proteins (LTP) (17) for extraction, we investigated whether various families of LTP might assist antigen presentation. We focused on the Vα14 NKT cell endosomal-dependent system to test the possible involvement of LTPs localized in the endocytic pathway, such as saposins (18) (Fig. 1D). These findings demonstrate a selective defect in the development of Vα14 NKT cells in the absence of prosaposin.Many NKT cell hybridomas can be activated in vitro to release interleukin-2 (IL-2) by coculture with fresh CD1d-expressing cells, such as thymocytes, which are...
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