Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD1d is a critical molecule for the presentation of lipid antigens to natural killer (NK) T cells. To investigate the molecular complexity of CD1d, alternatively spliced transcripts in peripheral blood mononuclear cells from three healthy subjects were analyzed by PCR and sequencing methods. We found eight alternatively spliced variants of the CD1D gene (V1-V8), seven of which are newly established variants (V2-V8). V1 and V4 are in-frame; however, the other six variants (V2, V3, V5-V8) are out-of-frame. V1, V2, V4, and V5 lack a beta(2)-microglobulin binding site (alpha3 domain), indicating the unstable presentation of the CD1d molecule on the surface. In V2 and V5, the transmembrane region is absent, supporting a soluble CD1d. In the V3-V8 variants, the antigen binding region (alpha1 and alpha2 domains) is partially defective, suggesting incomplete functional products. In contrast, the V1 and V2 transcripts bear the complete antigen binding site, resulting in functional proteins. Especially, the V2 splicing variant might function as an inhibitory soluble CD1d molecule and regulate the presentation of antigens on APC to NKT cells.
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PMID:Alternative splicing forms of the human CD1D gene in mononuclear cells. 1100 91

Experimental autoimmune encephalomyelitis (EAE) is a Th1 cell-mediated autoimmune disease that can be protected against by stimulating regulatory cells. Here we examined whether EAE can be purposefully modulated by stimulating Valpha14 NK T cells with the CD1d-restricted ligand alpha-galactosylceramide (alpha-GC). EAE induced in wild-type C57BL/6 (B6) mice was not appreciably altered by injection of alpha-GC. However, EAE induced in IL-4 knockout mice and IFN-gamma knockout mice was enhanced or suppressed by alpha-GC, respectively. This indicates that the IL-4 and IFN-gamma triggered by alpha-GC may play an inhibitory or enhancing role in the regulation of EAE. We next studied whether NK T cells of wild-type mice may switch their Th0-like phenotype toward Th1 or Th2. Notably, in the presence of blocking B7.2 (CD86) mAb, alpha-GC stimulation could bias the cytokine profile of NK T cells toward Th2, whereas presentation of alpha-GC by CD40-activated APC induced a Th1 shift of NK T cells. Furthermore, transfer of the alpha-GC-pulsed APC preparations suppressed or enhanced EAE according to their ability to polarize NK T cells toward Th2 or Th1 in vitro. These results have important implications for understanding the role of NK T cells in autoimmunity and for designing a therapeutic strategy targeting NK T cells.
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PMID:Costimulation-dependent modulation of experimental autoimmune encephalomyelitis by ligand stimulation of V alpha 14 NK T cells. 1112 51

Human chromosomes 1q21-q25, 6p21.3-22.2, 9q33-q34, and 19p13.1-p13.4 carry clusters of paralogous loci, to date best defined by the flagship 6p MHC region. They have presumably been created by two rounds of large-scale genomic duplications around the time of vertebrate emergence. Phylogenetically, the 1q21-25 region seems most closely related to the 6p21.3 MHC region, as it is only the MHC paralogous region that includes bona fide MHC class I genes, the CD1 and MR1 loci. Here, to clarify the genomic structure of this model MHC paralogous region as well as to gain insight into the evolutionary dynamics of the entire quadriplication process, a detailed analysis of a critical 1.7 megabase (Mb) region was performed. To this end, a composite, deep, YAC, BAC, and PAC contig encompassing all five CD1 genes and linking the centromeric +P5 locus to the telomeric KRTC7 locus was constructed. Within this contig a 1.1-Mb BAC and PAC core segment joining CD1D to FCER1A was fully sequenced and thoroughly analyzed. This led to the mapping of a total of 41 genes (12 expressed genes, 12 possibly expressed genes, and 17 pseudogenes), among which 31 were novel. The latter include 20 olfactory receptor (OR) genes, 9 of which are potentially expressed. Importantly, CD1, SPTA1, OR, and FCERIA belong to multigene families, which have paralogues in the other three regions. Furthermore, it is noteworthy that 12 of the 13 expressed genes in the 1q21-q22 region around the CD1 loci are immunologically relevant. In addition to CD1A-E, these include SPTA1, MNDA, IFI-16, AIM2, BL1A, FY and FCERIA. This functional convergence of structurally unrelated genes is reminiscent of the 6p MHC region, and perhaps represents the emergence of yet another antigen presentation gene cluster, in this case dedicated to lipid/glycolipid antigens rather than antigen-derived peptides.
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PMID:Genomic anatomy of a premier major histocompatibility complex paralogous region on chromosome 1q21-q22. 1133 75

The induction of peripheral tolerance via immune privileged sites such as the eye requires splenic colocalization of NKT cells and CD1d(+) tolerogenic F4/80(+) APCs, both of which are needed for the generation of CD8(+)-regulatory T (Tr) cells. Whereas tolerogenic APCs secrete the chemokine macrophage-inflammatory protein-2 for the purpose of recruiting NKT cells, the signals responsible for recruiting potential Tr cells and additional APCs to the spleen are not known. Here we examined the ability of CD1d-stimulated NKT cells to produce chemokines that can recruit other cells needed for tolerance. Our results show that NKT cells stimulated by either CD1d-transfected fibroblasts in vitro or CD1d(+) tolerogenic APCs both in vivo and ex vivo produced RANTES in a CD1d-dependent manner. The requirement for RANTES in tolerance was demonstrated by studies in which RANTES blockade in vivo prevented not only APC accumulation in the spleen but also the generation of CD8(+) Tr cells that suppress Th1 immunity. Thus, CD1d-restricted NKT cells provide critical signals for orchestrating the accumulation of cells needed for tolerance induction. These data expand our current knowledge of RANTES beyond its role in Th1 immune responses to show its importance in tolerance induction and add a novel aspect to our understanding of the role of NKT cells in tolerance. Understanding the precise mechanisms involved in tolerance induction may lead to more effective therapeutic strategies for autoimmunity and graft rejection.
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PMID:NKT cell-derived RANTES recruits APCs and CD8+ T cells to the spleen during the generation of regulatory T cells in tolerance. 1207 25

Despite more than a 10-fold increase in T cell numbers in G-CSF-mobilized peripheral blood stem cell (PBSC) grafts, incidence and severity of acute graft-vs-host disease (GVHD) are comparable to bone marrow transplantation. As CD1d-restricted, Valpha24+Vbeta11+ NKT cells have pivotal immune regulatory functions and may influence GVHD, we aimed to determine whether G-CSF has any effects on human NKT cells. In this study, we examined the frequency and absolute numbers of peripheral blood NKT cells in healthy stem cell donors (n = 8) before and following G-CSF (filgrastim) treatment. Effects of in vivo and in vitro G-CSF on NKT cell cytokine expression profiles and on responsiveness of NKT cell subpopulations to specific stimulation by alpha-galactosylceramide (alpha-GalCer) were assessed. Contrary to the effects on conventional T cells, the absolute number of peripheral blood NKT cells was unaffected by G-CSF administration. Furthermore, responsiveness of NKT cells to alpha-GalCer stimulation was significantly decreased (p < 0.05) following exposure to G-CSF in vivo. This hyporesponsiveness was predominantly due to a direct effect on NKT cells, with a lesser contribution from G-CSF-mediated changes in APC. G-CSF administration resulted in polarization of NKT cells toward a Th2, IL-4-secreting phenotype following alpha-GalCer stimulation and preferential expansion of the CD4+ NKT cell subset. We conclude that G-CSF has previously unrecognized differential effects in vivo on NKT cells and conventional MHC-restricted T cells, and effects on NKT cells may contribute to the lower than expected incidence of GVHD following allogeneic peripheral blood stem cell transplantation.
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PMID:Granulocyte colony-stimulating factor modulates alpha-galactosylceramide-responsive human Valpha24+Vbeta11+NKT cells. 1547 38

NKT cell activation plays an important role in regulating innate and adaptive immunity during infection. We have previously found that there is a dramatic reduction in the NKT cell population on day 3 after an acute lymphocytic choriomeningitis virus (LCMV) infection. In this study, we report that this loss continued for at least 3 months and was not simply due to internalization of the TCR. Concomitant with the decrease in NKT cells was an increase in the percentage of Annexin V(+) NKT cells that remained in vivo, suggesting that the reduction in NKT cells at these late stages post-infection occurred by activation-induced cell death. Interestingly, APC from LCMV-infected mice could activate NKT cells in vitro at higher levels than those from uninfected mice and was concomitant with an increase in apoptosis in NKT cells. However, this could not be blocked by mAb to murine CD1d, and APC from LCMV-infected (but not uninfected) CD1d1-deficient mice could also stimulate NKT cells. Collectively, our data suggest that the activation and subsequent long-term loss of NKT cells is a normal component of the host's antiviral immune response, and this occurs in a CD1d-independent manner.
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PMID:Long-term loss of canonical NKT cells following an acute virus infection. 1572 41

Va14Ja18 natural T (iNKT) cells are innate, immunoregulatory lymphocytes that recognize CD1d-restricted lipid Ags such as alpha-galactosylceramide (alpha GalCer). The immunoregulatory functions of iNKT cells are dependent upon either IFN-gamma or IL-4 production by these cells. We hypothesized that alpha GalCer presentation by different CD1d-positive cell types elicits distinct iNKT cell functions. In this study we report that dendritic cells (DC) play a critical role in alpha GalCer-mediated activation of iNKT cells and subsequent transactivation of NK cells. Remarkably, B lymphocytes suppress DC-mediated iNKT and NK cell activation. Nevertheless, alpha GalCer presentation by B cells elicits low IL-4 responses from iNKT cells. This finding is particularly interesting because we demonstrate that NOD DC are defective in eliciting iNKT cell function, but their B cells preferentially activate this T cell subset to secrete low levels of IL-4. Thus, the differential immune outcome based on the type of APC that displays glycolipid Ags in vivo has implications for the design of therapies that harness the immunoregulatory functions of iNKT cells.
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PMID:Distinct roles of dendritic cells and B cells in Va14Ja18 natural T cell activation in vivo. 1581 94

alpha-Galactosylceramide (alpha-GalCer) is a ligand of invariant Valpha14+ NKT cells and is presented by CD1d molecule on APC. NKT cells produce a large amount of Th1 and Th2 cytokines in response to alpha-GalCer-presented APC. In this study, we assessed whether alpha-GalCer could act as an effective nasal vaccine adjuvant for mucosal vaccine that would be capable of inducing systemic as well as mucosal immune responses. When alpha-GalCer was administered with OVA via the intranasal route to C57BL/6 and BALB/c mice, significant OVA-specific mucosal secretory IgA, systemic IgG, and CTL responses were induced with mixed Th1 and Th2 cytokine profiles seen in both strains of mice. Interestingly, as BALB/c mice were intranasally immunized with PR8 hemagglutinin Ag isolated from influenza virus A/PR/8/34 together with alpha-GalCer, significant protection was afforded against influenza viral infection. When alpha-GalCer was coimmunized with a replication-deficient live adenovirus to BALB/c mice, it significantly induced both humoral and cellular immune responses. In addition, intranasal administration of OVA with alpha-GalCer showed complete protection against EG7 tumor challenge in C57BL/6. The adjuvant effects induced by intranasal coadministration with alpha-GalCer were blocked in CD1d-/- mice, indicating that the immune responses were exclusively mediated by CD1d molecule on APC. Most interestingly, intranasally coadministered alpha-GalCer activated naive T cells and triggered them to differentiate into functional effector T cells when CFSE-labeled OT-1 cells were adoptively transferred into syngeneic mice. Overall, our results are the first to show that alpha-GalCer can act as a nasal vaccine adjuvant inducing protective immune responses against viral infections and tumors.
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PMID:alpha-Galactosylceramide can act as a nasal vaccine adjuvant inducing protective immune responses against viral infection and tumor. 1611 23

In this study we show that like MHC class I and class II molecules, cell surface CD1d expression on APC is regulated and affects T cell activation under physiological conditions. Although IFN-gamma alone is sufficient for optimum expression of MHC, CD1d requires two signals, one provided by IFN-gamma and a second mediated by microbial products or by the proinflammatory cytokine TNF. IFN-gamma-dependent CD1d up-regulation occurs on macrophages following infection with live bacteria or exposure to microbial products in vitro and in vivo. APC expressing higher CD1d levels more efficiently activate NKT cell hybridomas and primary NKT cells independently of whether the CD1d-restricted TCR recognizes foreign or self-lipid Ags. Our findings support a model in which CD1d induction regulates NKT cell activation.
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PMID:Interplay of cytokines and microbial signals in regulation of CD1d expression and NKT cell activation. 1614 2

NKT cells are thought of as a bridge between innate and adaptive immunity. In this study, we demonstrate that mouse NKT cells are activated in response to Escherichia coli LPS, and produce IFN-gamma, but not IL-4, although activation through their TCR typically induces both IL-4 and IFN-gamma production. IFN-gamma production by NKT cells is dependent on LPS-induced IL-12 and IL-18 from APC. LPS induced IFN-gamma production by NKT cells does not require CD1d-mediated presentation of an endogenous Ag and exposure to a combination of IL-12 and IL-18 is sufficient to activate them. In mice that are deficient for NKT cells, innate immune cells are activated less efficiently in response to LPS, resulting in the reduced production of TNF and IFN-gamma. We propose that in addition to acting as a bridge to adaptive immunity, NKT cells act as an early amplification step in the innate immune response and that the rapid and complete initiation of this innate response depends on the early production of IFN-gamma by NKT cells.
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PMID:Invariant NKT cells amplify the innate immune response to lipopolysaccharide. 1731 12


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