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NKT cells represent a distinct lineage of T cells that coexpress a conserved αβ 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 β-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., As with protein-derived antigens, lipids, glycolipids, and lipopeptides (either of microbial or self origin) can be recognized by TCRαβ-expressing T lymphocytes (1). Of these, NKT cells represent an unusual population [...]

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 [...]

To complete their maturation, most immature thymocytes depend on the simultaneous engagement of their antigen receptor αβ T cell receptor (TCR) and their CD4 or CD8 coreceptors with major histocompatibility complex class II or I ligands, respectively. However, a normal subset of mature αβ[TCR.sup.+] thymocytes did not follow these rules. These thymocytes expressed NK1.1 and a restricted set of αβ TCRs that are intrinsically class I-reactive because their positive selection was class I-dependent but CD8-independent. These cells were [CD4.sup.+] and [CD4.sup.-8.sup.-] but never [CD8.sup.+], because the presence of C caused negative selection. Thus, neither CD4 nor CD8 contributes signals that direct their maturation into the [CD4.sup.+] and [CD4.sup.-8.sup.-]lineages., During the positive selection of [CD4.sup.+8+] double-positive precursor thymocytes, cells bearing major histocompatibility complex (MHC) class I-specific αβ TCRs are recruited into the CD8 lineage, whereas cells bearing class II-specific [...]

CD1d-restricted autoreactive natural killer ([NK1.1.sup.+]) T cells function as regulatory cells in various disease conditions. Using improved tetramer tracking methodology, we identified a [NKI.1.sup.-] thymic precursor and followed its differentiation and emigration to tissues by direct cell transfer and in situ cell labeling studies. A major lineage expansion occurred within the thymus after positive selection and before NK receptor expression. Surprisingly, cytokine analysis of the developmental intermediates between [NK.sup.-] and [NK.sup.+] stages showed a T helper cell [T.sub.H]2 to [T.sub.H]1 conversion, suggesting that the regulatory functions of NK T cells may be developmentally controlled. These findings characterize novel thymic and postthymic developmental pathways that expand autoreactive cells and differentiate them into regulatory cells., In addition to mainstream CD4 and CD8 αβ T cells, the thymus produces specialized subsets of autoreactive regulatory cells, including CD1d-restricted [CD4.sup.+] and [CD4.sup.-][8.sup.-] (DN) NK T cells and major [...]

Immune responses dominated by interleukin-4 (IL-4)-producing T helper type 2 ([T.sub.H]2) cells or by interferon γ (IFN-γ)-producing T helper type 1 ([T.sub.H]1) cells express distinctive protection against infection with different pathogens. Interleukin-4 promotes the differentiation of naive CD4+ T cells into IL-4 producers and suppresses their development into IFN-γ producers. CD1 -specific splenic CD4+NK1.1+ T cells, a numerically minor population, produced IL-4 promptly on in vivo stimulation. This T cell population was essential for the induction of IL-4-producing cells and for switching to immunoglobulin E, an IL-4-dependent event, in response to injection of antibodies to immunoglobulin D., Interleukin-4 is a major determinant of the differentiation of naive T cells into IL-4-producing cells and has the capacity to suppress their differentiation into IFN-γ-producing cells[1], A potential source of [...]

Rare major histocompatibility complex (MHC) class I-like CD1-specific T cells have been isolated from human blood, but it has not been determined whether these clones are part of a defined subset of CD1-specific T cells selected during T cell development, or whether their recognition of CD1 is a fortuitous cross-reaction. In mice, an entire subset of αβ thymocytes with a unique phenotype was found to be CD1-specific. This particular subset, and its human counterpart, provide evidence that CD1 has a general role in s electing and interacting with specialized αβ T cells., Mouse NK[1.sup.+] T cells constitute up to 20% of the mature compartment of the thymus and are also found in most peripheral tissues, with particular frequency in bone marrow and [...]

In their search for the role of T cells in insulin-dependent diabetes mellitus (IDDM), Myra A. Lipes et al. (1) state that an intact T cell receptor (TCR) repertoire is [...]

Bacterial superantigens spur IgA secretion: Mucosal IgA is abundant and interacts with the gut microbiome. To examine microbial induction of IgA in humans, Bunker et al. screened microbiota from infants against mouse and human IgA. Unexpectedly, they saw a subset of samples bound IgA in a way that indicated the presence of superantigens, which bind T cell receptors or B cell receptors outside of the typical antigen-binding region, leading to nonspecific activation. Putative superantigens were identified in commensal members of Lachnospiraceae, which activated human VH3-positive B cells and induced IgA production in mice. These data identify commensal superantigens and suggest that they may be dominant forces behind IgA production in humans. IgA is prominently secreted at mucosal surfaces and coats a fraction of the commensal microbiota, a process that is critical for intestinal homeostasis. However, the mechanisms of IgA induction and the molecular targets of these antibodies remain poorly understood, particularly in humans. Here, we demonstrate that microbiota from a subset of human individuals encode two protein "superantigens" expressed on the surface of commensal bacteria of the family Lachnospiraceae such as Ruminococcus gnavus that bind IgA variable regions and stimulate potent IgA responses in mice. These superantigens stimulate B cells expressing human VH3 or murine VH5/6/7 variable regions and subsequently bind their antibodies, allowing these microbial organisms to become highly coated with IgA in vivo. These findings demonstrate a previously unappreciated role for commensal superantigens in host-microbiota interactions. Furthermore, as superantigen-expressing strains show an uneven distribution across human populations, they should be systematically considered in studies evaluating human B cell responses and microbiota during homeostasis and disease. [ABSTRACT FROM AUTHOR]

Fortuitously discovered in 1979 as the first human leukocyte antigens recognized by a monoclonal antibody (1), CD1 proteins are distant cousins of major histocompatibility complex (MHC) molecules that are encoded [...]

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 CD 1d-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. [ABSTRACT FROM AUTHOR]