Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06126 (CD1a)
 2,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Individual CD1-restricted T cells can recognize either endogenous or foreign lipid Ags, but the extent to which the same CD1-restricted TCR can react to both self and microbial lipids is unknown. In this study, we have identified CD1a-, CD1b-, and CD1c-restricted T cells from normal human donors that induce cytolysis and secrete copious IFN-gamma in response to self-CD1 expressed on monocyte-derived dendritic cells. Remarkably, microbial Ags presented by CD1 are even more potent agonists for these same T cells. The alphabeta T cell receptors from such clones are diverse and confer specificity for both self-CD1 and foreign lipid Ags. The dual reactivity of these CD1-restricted cells suggests that the capacity for rapid responses to inflammatory stimuli without memory coexists with the capacity for strong Ag-specific responses and the generation of memory in vivo.
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PMID:CD1a-, b-, and c-restricted TCRs recognize both self and foreign antigens. 1627 86

Post kala-azar dermal leishmaniasis (PKDL) is a dermatosis caused by persistence of Leishmania donovani parasites in the skin following apparently successful treatment of visceral leishmaniasis. The distribution of PKDL lesions in Sudanese patients often mirrors the clothing habits of those affected. It is most severe in or confined to the sun-exposed parts of the skin. It is well established that elimination of Leishmania parasites requires activation of parasitised macrophages by a Th1 immune response and that the latter is depressed by ultraviolet light (UVB). In this paper, we hypothesized that UVB light might be a key player in the pathogenesis of PKDL. This paper links observations made in the field with immunological data that are compatible with this hypothesis. We therefore investigated patients with PKDL immunologically for a possible role of UVB exposure in the pathogenesis of this condition. We marshal evidence that the changes in the tissues are compatible with the effects of UVB light and it is probable that UVB appears to be a key factor in the pathogenesis of PKDL. Immunopathologically the lesions were characterized by an influx of various inflammatory cells. The number of CD1a (Langerhans' cells) was decreased, they lost their dendrites, their HLA-DR and B7-1 expression was down regulated while B7-2 was expressed. Others have shown that Langerhans' cells with these features result from UVB exposure and that such cells are unable to present antigen to Th1 cells while retaining the capacity to present antigen to Th2 cells. Various cytokines known to be induced by UVB radiation could be demonstrated in PKDL lesions. Of these IL-10, TGF-beta, IL-12, IL-4 and TNF-alpha were found in different quantities. The Th-1 cytokine IFN-gamma was constantly present. The tissue origin of the Th-1 cells in PKDL is unknown. We believe that the antagonistic action of the different cytokines is the cause of the inflammation and chronicity of PKDL.
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PMID:The pathogenesis of post kala-azar dermal leishmaniasis from the field to the molecule: does ultraviolet light (UVB) radiation play a role? 1638 55

The CD1 family of proteins presents lipid Ags to T cells. Human CD1a, CD1b, and CD1c have been shown in humans to present mycobacterial lipid Ags. Cattle, like humans, are a natural host of several mycobacterial pathogens. In this study, we describe the CD1 family of genes in cattle (Bos taurus) and provide evidence that B. taurus expresses CD1a, CD1e, and multiple CD1b molecules, but no CD1c and CD1d molecules. In mice and humans, CD1d is known to present Ag to NKT cells, a T cell lineage that is characterized by a limited TCR repertoire, capable of rapidly secreting large amounts of IFN-gamma and IL-4. In cattle, two CD1D pseudogenes were found and no intact CD1D genes. Consistent with this, we found complete lack of reactivity to a potent, cross-reactive Ag for NKT cells in mice and humans, alpha-galactosylceramide. Our data suggest the absence of NKT cells in cattle. It remains open whether other cells with the NKT-like phenotype and functions are present in this species. With its functional CD1A and CD1B genes, B. taurus is well equipped to present Ags to CD1-restricted T cells other than NKT cells. Cattle can be used as a model to study group 1 CD1-restricted T cell immunity, including its role in the defense against mycobacterial infections that occur naturally in this species.
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PMID:The bovine CD1 family contains group 1 CD1 proteins, but no functional CD1d. 1658 84

Dendritic cells (DCs), which differentiate in vitro from peripheral blood monocytes (PBMOs) or bone marrow precursors, are a promising candidate for immunotherapy against cancer. The dog, which suffers common types of cancers along with humans, make an ideal large animal model for cancer studies. Monocyte-derived DCs in the dog have not been well characterized, however, since the appropriate condition for in vitro differentiation has not been established. To tackle this problem, we have developed a conditioned media by culturing T cells with immobilized anti-canine CD3 antibody, and sought to induce differentiation of DCs from PBMOs. When purified CD14+ PBMOs were cultured in the presence of 25% T cell conditioned medium (TCCM), the PBMOs increased size and had extended dendritic processes by day 12 of the culture. The cultured PBMOs were found to increase the expression of MHC class II and CD1a molecules, and significantly increased stimulatory activity for allogeneic T cells in the mixed leukocyte reaction. Moreover, the cells significantly increased their expression of IL-18 and IFN-gamma when stimulated with polyinosinic-polycytidylic acid (Poly (I:C)). The cells have a reduced phagocytic activity, which is a common defect in mature DCs. It follows from these results that TCCM does induce the differentiation of DCs from PBMOs.
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PMID:Generation of canine dendritic cells from peripheral blood monocytes without using purified cytokines. 1690 55

Dendritic cells (DCs) act as antigen presenting cells that bridge innate and adaptive immune systems with the unique capacity to initiate primary T-cell responses and efficiently stimulate memory responses. In pig, little information is available about these cells in secondary lymphoid organs, the place where T cell activation usually occurs. As increased knowledge on DC is a necessary prerequisite to further understand their role in response to microbial infection or in protection after vaccination, we investigated the DC types that would be present in tonsil, spleen and non-subcutaneous lymph nodes in the steady state. One population was composed of CD172a(+)CD11R1(+)CD1(+/-)CD80/86(+/-) cells and would correspond to conventional DCs (cDC), while the other one was composed of CD172a(+)CD4(+)CD1(+/-)CD80/86(+/-) cells and would correspond to plasmacytoid DCs (pDC). These subsets were also detected in blood but spleen was the tissue with the higher frequency of such DCs. In lymphoid organs, most of cDC and pDC were in an immature status, as revealed by the low percentage of cells expressing the co-stimulatory molecule CD80/86. However, expression of that marker by 5% of DCs in organs and up to 15% in blood, together with lower expression of CD1a and expression of CD208, would indicate a partial activation and/or semi-maturation. Interestingly, 8% of tonsil pDC and 15% of blood pDC were shown to secrete IFN-alpha, while 18-20% of cDC expressed TNF-alpha in these tissues. Both cell types also expressed IL-12 and IL-10 in the steady state. Measurements of IFN-alpha, TNF-alpha, IL-12 and IL-10 levels in serum confirmed their production within immune homeostasis, whereas IL-6, IL-18 and IFN-gamma could not be detected. Altogether, these data complete knowledge on porcine immune system cells and will be a useful tool for further in vivo studies on porcine DC role in peripheral tolerance induction and in immune responses to pathogens.
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PMID:Characterization of conventional and plasmacytoid dendritic cells in swine secondary lymphoid organs and blood. 1697 9

P-glycoprotein (P-gp) expressed on human antigen presenting cells (APC) regulates alloantigen-dependent T-cell activation, but the associated mechanisms are not well understood. Here we demonstrate that P-gp functions in IL-12-dependent monocyte differentiation into dendritic cell (DC) lineages during APC maturation, thereby regulating the capacity of myeloid-derived APCs to elicit alloimmune Th1 responses. Human CD14+ monocytes cultured in vitro in the presence of IL-4/GM-CSF differentiated into CD14(-) CD1A+ APCs of the immature DC phenotype. In contrast, P-gp blockade during differentiation inhibited CD1a induction, down-regulated CD80 expression, enhanced CD86 expression and induced CD68 expression. APCs differentiated in the presence of P-gp blockade stimulated alloimmune T-cell proliferation significantly less than controls and this effect was associated with 97% inhibition of Th1 IFN-gamma production, but preserved Th2 IL-5 secretion. MAb-mediated blockade of the P-gp transport substrate IL-12 in the course of APC differentiation also inhibited IFN-gamma production, while addition of rIL-12 to P-gp-blocked APC differentiation cultures significantly reversed this effect, demonstrating that P-gp functions in APC differentiation in part via IL-12 regulation. Our findings define a novel role for P-gp as a differentiation switch in APC maturation and resultant alloimmune Th1 responses, thereby identifying P-gp as a potential novel therapeutic target in allotransplantation.
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PMID:P-glycoprotein functions as a differentiation switch in antigen presenting cell maturation. 1708 70

Helicobacter pylori causes chronic gastric infection that affects the majority of the world's population. Despite generating an inflammatory response, the immune system usually fails to clear the infection. Since dendritic cells (DCs) play a pivotal role in shaping the immune response, we investigated the effects of H. pylori on DC function. We have demonstrated that H. pylori increased the expression of activation markers on DCs while upregulating the inhibitory B7 family molecule, PD-L1. Functionally, H. pylori-treated DCs resulted in the production of interleukin-10 (IL-10) and IL-23 but not of alpha interferon (IFN-alpha). While very little or no IL-12 was produced to H. pylori alone, simultaneous ligation of CD40 on DCs induced IL-12 release. We also demonstrated that DCs treated with H. pylori-induced IFN-gamma production by allogeneic naive T cells. However, stimulation of DCs with H. pylori for an extended period of time impaired their ability to produce cytokines after CD40 ligation and limited their ability to promote IFN-gamma release, suggesting that the DCs had become exhausted by the prolonged stimulation. The effect of chronic infection with H. pylori on DC function was further investigated by focusing on DC development. Demonstrating that monocytes differentiated into DCs in the presence of H. pylori exhibited an exhausted phenotype with an impaired ability to produce IL-12 and a downregulation of CD1a. Our results raise the possibility that in chronic H. pylori infection DCs become exhausted after prolonged antigen exposure leading to suboptimal Th1 development. This effect may contribute to persistence of H. pylori infection.
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PMID:Chronic exposure to Helicobacter pylori impairs dendritic cell function and inhibits Th1 development. 1710 59

IL-15 has recently been shown to induce the differentiation of functional dendritic cells (DCs) from human peripheral blood monocytes. Since DCs lay in close proximity to epithelial cells in the airway mucosa, we investigated whether airway epithelial cells release IL-15 in response to inflammatory stimuli and thereby induce differentiation and maturation of DCs. Alveolar (A549) and bronchial (BEAS-2B) epithelial cells produced IL-15 spontaneously and in a time- and dose-dependent manner after stimulation with IL-1beta, IFN-gamma, or TNF-alpha. Airway epithelial cell supernatants induced an increase of IL-15Ralpha gene expression in ex vivo monocytes, and stimulated DCs enhanced their IL-15Ralpha gene expression up to 300-fold. Airway epithelial cell-conditioned media induced the differentiation of ex vivo monocytes into partially mature DCs (HLA-DR+, DC-SIGN+, CD14+, CD80-, CD83+, CD86+, CCR3+, CCR6(+), CCR7-). Based on their phenotypic (CD123+, BDCA2+, BDCA4+, BDCA1(-), CD1a-) and functional properties (limited maturation upon stimulation with LPS and limited capacity to induce T cell proliferation), these DCs resembled plasmacytoid DCs. The effects of airway epithelial cell supernatants were largely blocked by a neutralizing monoclonal antibody to IL-15. Thus, our results demonstrate that airway epithelial cell-conditioned media have the capacity to differentiate monocytes into functional DCs, a process substantially mediated by epithelial-derived IL-15.
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PMID:Airway epithelial IL-15 transforms monocytes into dendritic cells. 1736 80

NKR-P2/NKG2D is the chief tumor recognition receptor of NK cells and some T cells, which recognizes stress inducible ligands on tumors and mediates cell activation. We have recently reported the involvement of NKR-P2 in rat dendritic cell (DC) activation. We demonstrate the potential of agonistic anti-NKR-P2 mAb (1A6), which mimics the NKR-P2 ligand and induces activation and maturation of DCs. Interaction of DCs with 1A6 enhances nitric oxide-mediated apoptosis in tumor cells. Cross-linking of NKR-P2 with mAb1A6 up-regulates MHC II, CD86, CD1a, antigen-presentation function and decreases endocytic activity of DC, thus drives DCs to play a pivotal role in adaptive immune responses. NKR-P2 cross-linking with 1A6 also induced the secretion of inflammatory cytokines, IL-1beta, tumor necrosis factor-alpha, IFN-gamma and IL-12 by DCs. Blocking of 1A6-mediated activation and maturation with inhibitors of PI3K, p38K and ERK1/2K suggests involvement of MAP kinase in signal transduction. 1A6 cross-linking activates nuclear factor kappa B, which acts as key executioner of DC activation. Administration of 1A6 antibody induces rapid regression and protective immune responses against transplantable tumors, suggesting mAb induced activation and maturation of DCs, leading to enhanced anti-tumor immune response.
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PMID:Cross-linking a mAb to NKR-P2/NKG2D on dendritic cells induces their activation and maturation leading to enhanced anti-tumor immune response. 1736 87

Dendritic cells (DC) excel at presenting antigen to T cells and thus make a key contribution to the induction of primary and secondary immune responses. Sinomenine has been used for centuries in the treatment of patients with autoimmune diseases as it possesses immunosuppressive and anti-inflammatory activities. However, the effect of sinomenine on the differentiation, maturation, and functionality of DC derived from monocytes has not been studied. We show here that DC differentiation is promoted when monocytes are treated with GM-CSF and IL-4 (IL-4) in the presence of sinomenine (200 microg/ml), as evidenced by the upregulation of CD1a while CD14 was decreased. In addition, incubation of immature DC with sinomenine significantly blunted lipopolysaccharide (LPS)-induced DC maturation, as shown by the reduction of expression of the maturation marker CD83 and co-stimulatory molecules, including CD86, B7-H1, and CD40. Moreover, sinomenine also prevented decreases in antigen (FITC-Dextran or Lucifer Yellow) uptake by LPS-treated DC. Mixed lymphocyte reactions (MLRs) revealed that sinomenine-treated DC impede the secretion of the cytokines IL-2 and IFN-gamma by co-cultured CD4(+) T cells. Therefore, modulation of DC differentiation, maturation, and functionality by sinomenine is of potential relevance to its immunomodulatory effects in controlling specific immune responses in autoimmune diseases, transplantation, and other immune-mediated conditions.
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PMID:Sinomenine promotes differentiation but impedes maturation and co-stimulatory molecule expression of human monocyte-derived dendritic cells. 1757 Mar 27


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