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1
Huang, Shouxiong, Tan-Yun Cheng, John Altman, and D. Branch Moody. "Comparative lipidomics reveals a global sampling of major cellular membrane lipids by human CD1 proteins (P5006)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 41.4. http://dx.doi.org/10.4049/jimmunol.190.supp.41.4.
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Abstract Human CD1 proteins have differentially shaped grooves and present bacterial or self lipid antigens to T cells, but it is unknown whether the pool of endogenous lipids are differently sampled by each type of CD1 proteins. We used recently established lipidomic approach to analyze the molecules extracted from human CD1a, CD1b, CD1c, and CD1d proteins. In the study, we demonstrated that this highly sensitive and accurate lipidomic approach detected more than one thousand diverse molecules defined by accurate mass retention time values, which represented hundreds of lipid species associated with CD1 proteins. More than fifty percent of these molecules were shared by all four types of CD1 proteins and additional thirty percent shared by two or three CD1 isoforms. Further mass spectrometry analyses of collision-induced dissociation showed that the molecules eluted from all four types of CD1 proteins mainly are lipids from subcellular membranes, including phospholipids of conventional, ether-linked, and lyso forms and sphingolipids. Surprisingly, CD1 isoforms with bigger grooves preferred to lipids with shorter chains, which can be explained by small spacer or scaffold lipids that bind together with antigens. Whereas previous studies argued that one lipid molecule blocks CD1 grooves, analogous to MHC class II-associated CLIP peptide, we conclude that CD1 proteins broadly sample cellular lipids and two small lipids are able to be adapted into a big groove.
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Kasinrerk, W., T. Baumruker, O. Majdic, W. Knapp, and H. Stockinger. "CD1 molecule expression on human monocytes induced by granulocyte-macrophage colony-stimulating factor." Journal of Immunology 150, no. 2 (January 15, 1993): 579–84. http://dx.doi.org/10.4049/jimmunol.150.2.579.
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Abstract In this paper we demonstrate that granulocyte-macrophage CSF (GM-CSF) specifically induces the expression of CD1 molecules, CD1a, CD1b and CD1c, upon human monocytes. CD1 molecules appeared upon monocytes on day 1 of stimulation with rGM-CSF, and expression was up-regulated until day 3. Monocytes cultured in the presence of LPS, FMLP, PMA, recombinant granulocyte-CSF, rIFN-gamma, rTNF-alpha, rIL-1 alpha, rIL-1 beta, and rIL-6 remained negative. The induction of CD1 molecules by rGM-CSF was restricted to monocytes, since no such effect was observed upon peripheral blood granulocytes, PBL, and the myeloid cell lines Monomac1, Monomac6, MV4/11, HL60, U937, THP1, KG1, and KG1A. CD1a mRNA was detectable in rGM-CSF-induced monocytes but not in those freshly isolated. SDS-PAGE and immunoblotting analyses of CD1a mAb VIT6 immunoprecipitate from lysate of rGM-CSF-activated monocytes revealed an appropriate CD1a polypeptide band of 49 kDa associated with beta 2-microglobulin. Expression of CD1 molecules on monocytes complements the distribution of these structures on accessory cells, and their specific induction by GM-CSF strengthens the suggestion that CD1 is a family of crucial structures required for interaction between accessory cells and T cells.
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Theodorou, I. D., L. Boumsell, C. F. Calvo, H. Gouy, H. M. Beral, and P. Debre. "CD1 stimulation of human T cell lines induces a rapid increase in the intracellular free Ca2+ concentration and the production of IL-2." Journal of Immunology 144, no. 7 (April 1, 1990): 2518–23. http://dx.doi.org/10.4049/jimmunol.144.7.2518.
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Abstract The effect of a battery of CD1 mAb on intracellular free Ca2+ concentration and IL-2 production has been examined on different T cell lines in this study. Both 0249F and NU-T2 two CD1b specific mAb tested, induced a rapid increase in the intracellular Ca2+ concentration on HPBALL T cells whereas only one (L161) among three different CD1c mAb (L161, 10C3, and M241) produced a similar effect. In contrast the addition of four different CD1a mAb directed against two different epitopic groups of this molecule were uneffective in modifying the intracellular Ca2+. Both L161 and 0249F also induced a comparable increase in the intracellular Ca2+ concentration on MOLT 4 and JURKAT, two other T cell lines of similar phenotype. The effect of L161 mAb on the IL-2 production of the IL-2 producing T cell line JURKAT was also examined. The association of the latter with PMA strongly induced the production of IL-2 on this cell model while either L161 or PMA alone had no effect. Although the natural ligand and the function of CD1 molecules are still unknown, the accumulation of these data strongly suggest that CD1b and CD1c might represent two activatory pathways for immature T cells operating before the classical CD2 and CD3 activation pathways.
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Li, Sha, Hak-Jong Choi, Sharmila Shanmuganad, and Chyung-Ru Wang. "Phenotypic and functional characterization of group 1 CD1-restricted autoreactive T cells in a transgenic mouse model expressing human group 1 CD1 and a CD1b-specific T cell receptor (36.31)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 36.31. http://dx.doi.org/10.4049/jimmunol.184.supp.36.31.
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Abstract Unlike other MHC molecules, the CD1 family presents self and foreign lipid antigens to multiple T cell subsets. In humans, this family consists of group 1 CD1 molecules CD1a, b and c and group 2 molecule CD1d. While CD1d-restricted NKT cells have been well-studied, our knowledge of the development and function of group 1 CD1-restricted T cells has been limited by the lack of a suitable animal model. We have generated double transgenic mice (hCD1Tg/HJ1Tg) that express the human group 1 CD1 proteins in a pattern similar to that observed in humans in addition to a TCR from a CD1b-restricted autoreactive T cell clone. Like NKT cells, the majority of HJ1Tg T cells that develop in hCD1Tg/HJ1Tg mice express NK markers and exhibit an activated phenotype. In addition, HJ1Tg T cells are highly enriched in the liver. The development of HJ1Tg T cells with the NKT cell phenotype is group 1 CD1-dependent, as NK1.1+ HJ1Tg T cells are absent in HJ1Tg mice that lack the human group 1 CD1 genes. Upon stimulation with group 1 CD1-expressing dendritic cells, HJ1Tg T cells primarily secrete proinflammatory cytokines, including IFN-γ, IL-17A, IL-6 and MCP-1. These cytokine productions can be further enhanced in the presence of TLR agonists, a phenomenon also observed in autoreactive NKT cells. The similarities between the phenotype and functional properties of HJ1Tg T cells and NKT cells suggest that these two autoreactive T cell subsets may play similar immunological roles.
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Blumberg, R. S., C. Terhorst, P. Bleicher, F. V. McDermott, C. H. Allan, S. B. Landau, J. S. Trier, and S. P. Balk. "Expression of a nonpolymorphic MHC class I-like molecule, CD1D, by human intestinal epithelial cells." Journal of Immunology 147, no. 8 (October 15, 1991): 2518–24. http://dx.doi.org/10.4049/jimmunol.147.8.2518.
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Abstract The human CD1 locus encodes three nonpolymorphic MHC class I-like cell surface glycoproteins, CD1a-c, which are expressed primarily by immature thymocytes. A mAb and antipeptide antiserum were utilized to determine the tissue distribution of a fourth CD1 molecule, CD1d. Within the lymphoid lineage, CD1d was expressed on B cells but not on thymocytes. Immunoperoxidase staining of fresh frozen intestinal tissues demonstrated that the majority of intestinal epithelial cells, with the exception of cells at the base of some crypts, expressed CD1d. The CD1d staining was observed in the cytoplasm and along the basolateral membranes of the epithelial cells. The intestinal epithelial cell expression of CD1d was confirmed by immunoblotting with a CD1d antipeptide antiserum. Further immunoperoxidase studies indicated that CD1d, unlike murine CD1, was also expressed by nonlymphoid tissues outside of the gastrointestinal tract. The expression of CD1d outside the lymphoid and myeloid lineages clearly distinguishes this molecule from CD1a-c and suggests that it may serve a distinct function. The prominent expression of CD1d by intestinal epithelial cells suggests that this molecule may be an important ligand for T lymphocytes within the gut-associated lymphoid tissue.
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Gansert, Jennifer L., Kayvon R. Niazi, Maria T. Ochoa, Peter A. Sieling, and Robert L. Modlin. "Endosomal Targeting Sequences from Non-Classical Antigen Presenting Molecules Can Direct Antigens into the MIIC and Other Antigen Processing Compartments." Blood 104, no. 11 (November 16, 2004): 1357. http://dx.doi.org/10.1182/blood.v104.11.1357.1357.
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Abstract The ultimate goal of these studies is to enhance the development of MHC class II-restricted helper T cell responses that are required for effective and durable immunotherapy. In order to optimize the processing and presentation of MHC class II-restricted epitopes, we are using a differential targeting strategy that relies upon the unique endosomal targeting sequences from the individual isoforms of the CD1 family of non-classical antigen presenting molecules. Distinct endosomal compartments differ with respect to pH and resident proteases. MHC class II molecules can load antigen in each of the different endosomal compartments. This is in addition to the traditional antigen loading compartment, MIIC. Therefore, by forcing the expression of a tumor antigen across different endosomal compartments, we hope to maximize the number of successfully processed epitopes. To achieve this, we have developed a PCR-based strategy to link the leader, transmembrane, and endosomal targeting sequences from the four different human CD1 isoforms, CD1a-d, to DNA encoding for a surrogate antigen, green fluorescent protein (GFP). Using this strategy, we have demonstrated that fusion of individual CD1 tails to the sequence for GFP resulted in four distinct expression patterns in HELA cells transfected with these constructs. Using immunofluorescent staining and confocal laser microscopy, we determined the pattern of antigen expression in various endosomal compartments. GFP variably colocalized with recycling endosomes (ARF-6), early endosomes (CD71, transferrin receptor), late endosomes (CD63), and late endosomes/lysosmes/MIIC (CD107a, LAMP-1). Three of the four CD1 tails also resulted in co-expression of GFP with the MHC class II molecule, HLA-DR. The expression pattern for each CD1 tail is shown in Table 1. These experiments validate the feasibility of the CD1 targeting approach. Current studies are underway to apply this strategy to the leukemia antigen, WT1, using recently completed and sequenced WT1/CD1 fusion constructs. ARF-6 CD71 CD63 CD107a CD1a −/+ − − − CD1b −/+ − + ++ CD1c + −/+ + ++ CD1d + −/+ − + Table 1. Pattern of GFP/CD1 fusion expression in different endosomal compartments. Fusion of the endosomal targeting sequences from human CD1 molecules to the model antigen, GFP, results in different patterns of antigen expression within distinct endosomal compartments. The degree of colocalization between GFP and the indicated markers of endosomal compartments is represented as follows: (−), no colocalization; (−/+), infrequent colocalization; (+), frequent colocalization; (++), extensive colocalization.
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Guo, Tingxi, Edward M. Y. Koo, and Naoto Hirano. "A Subset of Human Autoreactive CD1c-Restricted T Cells Preferentially Express TRBV4-1+ TCRs and Recognize Phospholipids." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 52.6. http://dx.doi.org/10.4049/jimmunol.198.supp.52.6.
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Abstract Unlike the highly polymorphic, peptide-presenting conventional MHC molecules, CD1 consists of a family of monomorphic, lipid-presenting proteins. Recent studies have revealed the molecular basis of mycobacterial lipid recognition by CD1a-c-restricted T cells. In addition to foreign lipids, subsets of CD1a-c-restricted T cells recognize self-lipids, which may have implications for human diseases such as autoimmunity and cancer. And yet, the molecular identity of these self-reactive T cells remains largely elusive. In this study, using a novel CD1c+ artificial antigen-presenting cell (aAPC)-based system, we have isolated human CD1c-restricted autoreactive T cells and characterized them at the molecular level. By employing the human cell line K562, deficient in MHC class I/II and CD1 expression, as a backbone, we generated an aAPC expressing CD1c as the sole antigen-presenting molecule with costimulatory molecules, CD80 and CD83. When stimulated with this CD1c+ aAPC endogenously presenting self-lipids, a subpopulation of primary human CD4+ T cells from multiple donors consistently upregulated CD154 (CD40L) in a CD1c-specific manner. These activated CD4+ T cells preferentially expressed TRBV4-1+ TCRs. Interestingly, TRAV usage and CDR3 sequences of these TRBV4-1+ T cells were diverse. Clonotypic analyses of the reconstituted TRBV4-1+ TCRs demonstrated that the heterogeneity of the CDR3 sequences greatly impacted the strength of CD1c-restricted autoreactivity. Furthermore, cell-free assays using recombinant CD1c loaded with distinct lipids identified several phospholipid species as potential self-ligands. These data provide new insights into the molecular identity of human autoreactive CD1c-restricted T cells.
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Amiot, M., A. Bernard, B. Raynal, W. Knapp, C. Deschildre, and L. Boumsell. "Heterogeneity of the first cluster of differentiation: characterization and epitopic mapping of three CD1 molecules on normal human thymus cells." Journal of Immunology 136, no. 5 (March 1, 1986): 1752–58. http://dx.doi.org/10.4049/jimmunol.136.5.1752.
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Abstract In humans, the presence of two non-HLA class 1-like molecules, whose expression, similar to murine Tla, is restricted to cortical thymocytes, has been shown with monoclonal antibodies defining the first cluster of differentiation (CD1). We report here with the use of 12 anti-CD1 antibodies and a combination of technical approaches, the characterization of a third CD1 molecule. We show that we can presently define seven different epitopes on the three CD1 molecules: four epitopes are restricted to the 49,000 dalton molecule, two epitopes to the 45,000 dalton molecule, and one epitope to the 43,000 dalton molecule. We show that the association of the newly identified 45,000 dalton heavy chain with human beta2-microglobulin is weak. In addition we show the presence of a fourth non-HLA class I molecular species on the surface of normal human thymus cells.
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Delia, D., G. Cattoretti, N. Polli, E. Fontanella, A. Aiello, R. Giardini, F. Rilke, and G. Della Porta. "CD1c but neither CD1a nor CD1b molecules are expressed on normal, activated, and malignant human B cells: identification of a new B-cell subset." Blood 72, no. 1 (July 1, 1988): 241–47. http://dx.doi.org/10.1182/blood.v72.1.241.241.
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Abstract The CD1 cluster of monoclonal antibodies (MoAbs) CD1a, CD1b, and CD1c, identifies molecules that are differentially expressed on hematopoietic and nonhematopoietic tissues. Our earlier finding that the mantle zone (MZ) but not the germinal center (GC) of normal lymph nodes (LN) is CD1c+, CD1a-, and CD1b- prompted us to further investigate the expression of these molecules on normal, activated, and malignant B cells. We report that blood and spleen contain CD1c+ B cells that account for 49% +/- 20.4% (mean +/- SD) and 50.9% +/- 4.4% of the total B cell population, respectively. CD1a- and CD1b-specific MoAbs are unreactive with both B and T cells; these latter are CD1c- as well. When CD1c+ and CD1c- B cells are activated in vitro, the CD1c molecule is upregulated in the former subset and induced de novo in the latter. Conversely, activated blood T cells remain CD1c-. Neither CD1a nor CD1b molecules are detected on activated T and B lymphocytes. At ultrastructural level, the CD1c+ B cells exhibit distinctive features, namely, condensed chromatin with or without a nucleolus and a unique cluster of cytoplasmic vesicles and organelles; the number of nucleolated cells is higher in the spleen (95%) than in the tonsil (40%) or blood (5%). These findings further confirm the similarity between blood and MZ B cells. The CD1c expression assessed on 27 B-cell chronic lymphocytic leukemias (B-CLL) and 46 B non-Hodgkin's lymphomas (B-NHL) was detected on 41% and 32% of cases, respectively; the latter comprised four follicular and 11 diffuse histotypes. The Burkitt's lymphomas were CD1c-negative. The B-cell neoplasms were all CD1a- and, except for four with a weak cytoplasmic staining, all CD1b- as well. The clear-cut CD1c distribution in normal LN (MZ+, GC-) contrasted with the evidence that some B-NHL cells of GC origin (eg, follicular with predominantly small cleaved cells) were CD1c+. Overall, the finding that CD1c expression is restricted to a fraction of B cells present in lymphoid organs and in peripheral blood indicates that CD1c is a powerful marker for the identification and dissection of B-cell subsets whose functional properties can now be evaluated.
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Delia, D., G. Cattoretti, N. Polli, E. Fontanella, A. Aiello, R. Giardini, F. Rilke, and G. Della Porta. "CD1c but neither CD1a nor CD1b molecules are expressed on normal, activated, and malignant human B cells: identification of a new B-cell subset." Blood 72, no. 1 (July 1, 1988): 241–47. http://dx.doi.org/10.1182/blood.v72.1.241.bloodjournal721241.
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The CD1 cluster of monoclonal antibodies (MoAbs) CD1a, CD1b, and CD1c, identifies molecules that are differentially expressed on hematopoietic and nonhematopoietic tissues. Our earlier finding that the mantle zone (MZ) but not the germinal center (GC) of normal lymph nodes (LN) is CD1c+, CD1a-, and CD1b- prompted us to further investigate the expression of these molecules on normal, activated, and malignant B cells. We report that blood and spleen contain CD1c+ B cells that account for 49% +/- 20.4% (mean +/- SD) and 50.9% +/- 4.4% of the total B cell population, respectively. CD1a- and CD1b-specific MoAbs are unreactive with both B and T cells; these latter are CD1c- as well. When CD1c+ and CD1c- B cells are activated in vitro, the CD1c molecule is upregulated in the former subset and induced de novo in the latter. Conversely, activated blood T cells remain CD1c-. Neither CD1a nor CD1b molecules are detected on activated T and B lymphocytes. At ultrastructural level, the CD1c+ B cells exhibit distinctive features, namely, condensed chromatin with or without a nucleolus and a unique cluster of cytoplasmic vesicles and organelles; the number of nucleolated cells is higher in the spleen (95%) than in the tonsil (40%) or blood (5%). These findings further confirm the similarity between blood and MZ B cells. The CD1c expression assessed on 27 B-cell chronic lymphocytic leukemias (B-CLL) and 46 B non-Hodgkin's lymphomas (B-NHL) was detected on 41% and 32% of cases, respectively; the latter comprised four follicular and 11 diffuse histotypes. The Burkitt's lymphomas were CD1c-negative. The B-cell neoplasms were all CD1a- and, except for four with a weak cytoplasmic staining, all CD1b- as well. The clear-cut CD1c distribution in normal LN (MZ+, GC-) contrasted with the evidence that some B-NHL cells of GC origin (eg, follicular with predominantly small cleaved cells) were CD1c+. Overall, the finding that CD1c expression is restricted to a fraction of B cells present in lymphoid organs and in peripheral blood indicates that CD1c is a powerful marker for the identification and dissection of B-cell subsets whose functional properties can now be evaluated.
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Chun, Taehoon, Kai Wang, Federico A. Zuckermann, and H. Rex Gaskins. "Molecular Cloning and Characterization of a Novel CD1 Gene from the Pig." Journal of Immunology 162, no. 11 (June 1, 1999): 6562–71. http://dx.doi.org/10.4049/jimmunol.162.11.6562.
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Abstract Much effort is underway to define the immunological functions of the CD1 multigene family, which encodes a separate lineage of Ag presentation molecules capable of presenting lipid and glycolipid Ags. To identify porcine CD1 homologues, a cosmid library was constructed and screened with a degenerate CD1 α3 domain probe. One porcine CD1 gene (pCD1.1) was isolated and fully characterized. The pCD1.1 gene is organized similarly to MHC class I and other CD1 genes and contains an open reading frame of 1020 bp encoding 339 amino acids. Expression of pCD1.1 mRNA was observed in CD3− thymocytes, B lymphocytes, and tissue macrophages and dendritic cells. The pCD1.1 cDNA was transfected into Chinese hamster ovary cells, and subsequent FACS analysis demonstrated that mAb 76-7-4, previously suggested to be a pig CD1 mAb, recognizes cell surface pCD1.1. Structurally, the pCD1.1 α1 and α2 domains are relatively dissimilar to those of other CD1 molecules, whereas the α3 domain is conserved. Overall, pCD1.1 bears the highest similarity with human CD1a, and the ectodomain sequences characteristically encode a hydrophobic Ag-binding pocket. Distinct from other CD1 molecules, pCD1.1 contains a putative serine phosphorylation motif similar to that found in human, pig, and mouse MHC class Ia molecules and to that found in rodent, but not human, MHC class-I related (MR1) cytoplasmic tail sequences. Thus, pCD1.1 encodes a molecule with a conventional CD1 ectodomain and an MHC class I-like cytoplasmic tail. The unique features of pCD1.1 provoke intriguing questions about the immunologic functions of CD1 and the evolution of Ag presentation gene families.
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Souter, M. N., C. V. Nguyen-Robertson, F. J. Ross, S. J. J. Reddiex, J. Waddington, I. Van Rhijn, S. B. G. Eckle, et al. "Identification and characterization of CD1-restricted T cells." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 206.6. http://dx.doi.org/10.4049/jimmunol.196.supp.206.6.
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Abstract Most studies of T cells have focused on those that respond to foreign peptides. However, other specialized populations of T cells exist that recognize lipid antigens and make up a substantial component of the human immune system. These lipid reactive T cells recognize antigens presented by antigen presentation molecules from the CD1 family. Four CD1 molecules exist (CD1a, CD1b, CD1c and CD1d), and each is capable of presenting a unique repertoire of lipids antigens to T cells. Much of what we have learned about lipid reactive T cells stems from studies of CD1d restricted NKT cells as these are present is both mice and humans and can be detected using CD1d/α-GalCer tetramers. In contrast, our understanding of the biology of CD1a, CD1b, CD1c restricted T cells is relatively limited. However, the recent generation of CD1a, CD1b and CD1c tetramers is helping with the identification and characterisation of these CD1-restricted T cells. We have produced CD1 tetramers loaded with mammalian self-lipids or lipid antigens from Mycobacterium tuberculosis. In conjunction, with a tetramer-based enrichment method, we have successfully identified both autoreactive and microbial lipid antigen specific T cells from healthy human blood. We reveal the phenotypic characteristics of these CD1-restricted T cells and used CD1 mutagenesis to provide new insight into TCR recognition of CD1-lipid antigen complexes. Collectively, these studies will serve as a basis for future studies of lipid reactive T cells in health and disease.
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Brossay, Laurent, Shabnam Tangri, Mark Bix, Susanna Cardell, Richard Locksley, and Mitchell Kronenberg. "Mouse CD1-Autoreactive T Cells Have Diverse Patterns of Reactivity to CD1+ Targets." Journal of Immunology 160, no. 8 (April 15, 1998): 3681–88. http://dx.doi.org/10.4049/jimmunol.160.8.3681.
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Abstract Humans and mice contain significant populations of T cells that are reactive for autologous CD1 molecules. Using a panel of five mouse CD1 (mCD1)-autoreactive T cell hybridomas, we show here that this autoreactivity does not correlate with the level of CD1 expression. In some cases, these autoreactive T cells can distinguish between different cell types that express the same CD1 molecule, suggesting that some factor in addition to CD1 expression is critical for autoreactive T cell stimulation. To determine whether a CD1-bound ligand may be required, we expressed mutant mCD1 molecules that are defective for the putative endosomal localization sequence in the cytoplasmic domain. We demonstrate that mCD1, like its human CD1 homologues, is found in endosomes, and that it colocalizes extensively with the DM molecule. We further demonstrate, by site-directed mutagenesis, that the tyrosine in the cytoplasmic sequence is required for this endosomal localization. A T cell hybrid expressing Vβ8 and Vα14, the major TCR expressed by NK1+ T cells, exhibited greatly diminished reactivity to mutant CD1 molecules that do not traffic through endosomes, although the reactivity of other T cell hybrids to this mutant was not greatly affected. Therefore, we propose that at least some of the autoreactive T cells require endosomally derived CD1-bound ligands, and that they are capable of distinguishing between a diverse set of such self-ligands, which might be either autologous lipoglycans or peptides.
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Barcena, A., MO Muench, AH Galy, J. Cupp, MG Roncarolo, JH Phillips, and H. Spits. "Phenotypic and functional analysis of T-cell precursors in the human fetal liver and thymus: CD7 expression in the early stages of T- and myeloid-cell development." Blood 82, no. 11 (December 1, 1993): 3401–14. http://dx.doi.org/10.1182/blood.v82.11.3401.3401.
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Abstract It has been proposed that the CD7 molecule is the first antigen expressed on the membrane of cells committed to the T-cell lineage during human fetal T-cell ontogeny. To further identify the pre-T cell subpopulation that migrates to the thymus early in ontogeny, we analyzed the phenotypic and functional characteristics of the fetal liver populations separated on the basis of CD7 expression. Three populations expressing different levels of CD7 were observed: CD7bright, CD7dull, and CD7-. A CD7bright population depleted of mature T, B, and myeloid cells (lineage negative, lin-) and mostly composed of CD56+ CD34- natural killer cells did not mature into T cells in a fetal thymic organ culture (FTOC) assay and was devoid of myeloid progenitors in a clonal colony-forming cell assay. In contrast, the CD7-/dull CD34+ lin- populations were capable of differentiating into phenotypically mature T cells after injection into FTOC and contained early myeloid progenitors. Here we phenotypically compared the fetal liver CD7 populations with the most immature fetal thymic subset that differentiated in the FTOC assay, namely the triple negative (TN, CD3- CD4-CD8-) thymocytes. Fetal TN lin- expressed high levels of CD34 marker and were further subdivided by their expression of CD1 antigen, because CD1- TN thymocytes express higher levels of CD34 antigen compared with CD1+ TN cells. CD1- lin -TN thymocytes are characterized by expressing high levels of CD2, CD7, and CD34 markers and dull levels of CD5, CD10, and CD28 molecules. We could not find fetal liver pre-T cells with a phenotype equivalent to that of TN thymocytes. Our data show that CD7 does not necessarily identify T-cell precursors during fetal T-cell development and strongly support the hypothesis that the acquisition of early T-cell markers as CD2, CD28, and CD5 molecules on the cell surface of T-cell progenitors takes place intrathymically.
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Barcena, A., MO Muench, AH Galy, J. Cupp, MG Roncarolo, JH Phillips, and H. Spits. "Phenotypic and functional analysis of T-cell precursors in the human fetal liver and thymus: CD7 expression in the early stages of T- and myeloid-cell development." Blood 82, no. 11 (December 1, 1993): 3401–14. http://dx.doi.org/10.1182/blood.v82.11.3401.bloodjournal82113401.
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It has been proposed that the CD7 molecule is the first antigen expressed on the membrane of cells committed to the T-cell lineage during human fetal T-cell ontogeny. To further identify the pre-T cell subpopulation that migrates to the thymus early in ontogeny, we analyzed the phenotypic and functional characteristics of the fetal liver populations separated on the basis of CD7 expression. Three populations expressing different levels of CD7 were observed: CD7bright, CD7dull, and CD7-. A CD7bright population depleted of mature T, B, and myeloid cells (lineage negative, lin-) and mostly composed of CD56+ CD34- natural killer cells did not mature into T cells in a fetal thymic organ culture (FTOC) assay and was devoid of myeloid progenitors in a clonal colony-forming cell assay. In contrast, the CD7-/dull CD34+ lin- populations were capable of differentiating into phenotypically mature T cells after injection into FTOC and contained early myeloid progenitors. Here we phenotypically compared the fetal liver CD7 populations with the most immature fetal thymic subset that differentiated in the FTOC assay, namely the triple negative (TN, CD3- CD4-CD8-) thymocytes. Fetal TN lin- expressed high levels of CD34 marker and were further subdivided by their expression of CD1 antigen, because CD1- TN thymocytes express higher levels of CD34 antigen compared with CD1+ TN cells. CD1- lin -TN thymocytes are characterized by expressing high levels of CD2, CD7, and CD34 markers and dull levels of CD5, CD10, and CD28 molecules. We could not find fetal liver pre-T cells with a phenotype equivalent to that of TN thymocytes. Our data show that CD7 does not necessarily identify T-cell precursors during fetal T-cell development and strongly support the hypothesis that the acquisition of early T-cell markers as CD2, CD28, and CD5 molecules on the cell surface of T-cell progenitors takes place intrathymically.
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Raftery, Martin J., Manuel Hitzler, Florian Winau, Thomas Giese, Bodo Plachter, Stefan H. E. Kaufmann, and Günther Schönrich. "Inhibition of CD1 Antigen Presentation by Human Cytomegalovirus." Journal of Virology 82, no. 9 (February 20, 2008): 4308–19. http://dx.doi.org/10.1128/jvi.01447-07.
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ABSTRACT The betaherpesvirus human cytomegalovirus (HCMV) encodes several molecules that block antigen presentation by the major histocompatibility complex (MHC) proteins. Humans also possess one other family of antigen-presenting molecules, the CD1 family; however, the effect of HCMV on CD1 expression is unknown. The majority of CD1 molecules are classified on the basis of homology as group 1 CD1 and are present almost exclusively on professional antigen-presenting cells such as dendritic cells, which are a major target for HCMV infection and latency. We have determined that HCMV encodes multiple blocking strategies targeting group 1 CD1 molecules. CD1 transcription is strongly inhibited by the HCMV interleukin-10 homologue cmvIL-10. HCMV also blocks CD1 antigen presentation posttranscriptionally by the inhibition of CD1 localization to the cell surface. This function is not performed by a known HCMV MHC class I-blocking molecule and is substantially stronger than the blockage induced by herpes simplex virus type 1. Antigen presentation by CD1 is important for the development of the antiviral immune response and the generation of mature antigen-presenting cells. HCMV present in antigen-presenting cells thus blunts the immune response by the blockage of CD1 molecules.
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Behar, S. M., S. A. Porcelli, E. M. Beckman, and M. B. Brenner. "A pathway of costimulation that prevents anergy in CD28- T cells: B7-independent costimulation of CD1-restricted T cells." Journal of Experimental Medicine 182, no. 6 (December 1, 1995): 2007–18. http://dx.doi.org/10.1084/jem.182.6.2007.
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A class of molecules that is expressed on antigen presenting cells, exemplified by CD80 (B7), has been found to provide a necessary costimulatory signal for T cell activation and proliferation. CD28 and CTLA4 are the B7 counterreceptors and are expressed on the majority of human CD4+ T cells and many CD8+ T cells. The signal these molecules mediate is distinguished from other costimulatory signals by the finding that T cell recognition of antigen results in a prolonged state of T cell unresponsiveness or anergy, unless these costimulatory molecules are engaged. However, nearly half of the CD8+ and CD4-CD8- T cells lack CD28, and the costimulatory signals required for the activation of such cells are unknown. To understand the pathways of activation used by CD28- T cells, we have examined the costimulatory requirements of antigen-specific CD4-CD8- TCR(+)-alpha/beta circulating T cells that lack the expression of CD28. We have characterized two T cell lines, DN1 and DN6, that recognize a mycobacterial antigen, and are restricted not by major histocompatibility complex class I or II, but by CD1b or CD1c, two members of a family of major histocompatibility complex-related molecules that have been recently implicated in a distinct pathway for antigen presentation. Comparison of antigen-specific cytolytic responses of the DN1 and DN6 T cell lines against antigen-pulsed CD1+ monocytes or CD1+ B lymphoblastoid cell lines (B-LCL) demonstrated that these T cells recognized antigen presented by both types of cells. However, T cell proliferation occurred only when antigen was presented by CD1+ monocytes, indicating that the CD1+ monocytes expressed a costimulatory molecule that the B-LCL transfectants lacked. This hypothesis was confirmed by demonstrating that the T cells became anergic when incubated with the CD1(+)-transfected B-LCL in the presence of antigen, but not in the absence of antigen. The required costimulatory signal occurred by a CD28-independent mechanism since both the CD1+ monocytes and CD1+ B-LCL transfectants expressed B7-1 and B7-2, and DN1 and DN6 lacked surface expression of CD28. We propose that these data define a previously unrecognized pathway of costimulation for T cells distinct from that involving CD28 and its counterreceptors. We suggest that this B7-independent pathway plays a crucial role in the activation and maintenance of tolerance of at least a subset of CD28- T cells.
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Rizvi, Zaigham, Niti Puri, and Rajiv Saxena. "Evidence of a functional CD1d lipid antigen presentation pathway in murine alveolar epithelial cells (APP3P.108)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 113.9. http://dx.doi.org/10.4049/jimmunol.194.supp.113.9.
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Abstract Lipid antigen presentation by CD1 molecule is an evolutionary conserved pathway that elicits rapid yet efficient cytotoxic response against fast mutating pathogens. CD1d molecule, the only isoform of CD1 family in mouse, has been shown to recognise important component of the Mycobacterium tuberculosis (Mtb) cell wall like phosphatidylinositol mannosides. We have recently shown that alveolar epithelial cells (AECs) present Mycobacterium bovis - BCG (an avirulent model for Mtb infection) antigens to sensitized Th cells in vitro, however, it remains unexplored whether AECs can also participate in the presentation of lipid antigens through CD1d pathway; that is, so far, know to operate only in professional antigen presenting cells like dendritic cells (DCs) and B cells. We started by establishing the expression of CD1d on LA4 (mouse airway epithelial) cell line and murine AECs by flow cytometry and immuno-histochemistry. qPCR showed significant up-regulation of mRNA expression of some of the crucial molecules involved in CD1d pathway in AECs upon BCG infection. The protein CD1d expression was also found to be boosted upon BCG infection. Finally, a functional CD1d antigen presentation by AECs (in vitro) was shown by using α-GalactosylCeramide (α-GalCer) antigen as model. Our findings suggest that AECs are capable of lipid antigen presentation through the CD1d pathway and this ability of AECs may contribute to the immune defences against pathogens like Mtb.
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Maître, Blandine, Catherine Angénieux, Virginie Wurtz, Emilie Layre, Martine Gilleron, Anthony Collmann, Sabrina Mariotti, et al. "The assembly of CD1e is controlled by an N-terminal propeptide which is processed in endosomal compartments." Biochemical Journal 419, no. 3 (April 14, 2009): 661–68. http://dx.doi.org/10.1042/bj20082204.
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CD1e displays unique features in comparison with other CD1 proteins. CD1e accumulates in Golgi compartments of immature dendritic cells and is transported directly to lysosomes, where it is cleaved into a soluble form. In these latter compartments, CD1e participates in the processing of glycolipid antigens. In the present study, we show that the N-terminal end of the membrane-associated molecule begins at amino acid 20, whereas the soluble molecule consists of amino acids 32–333. Thus immature CD1e includes an N-terminal propeptide which is cleaved in acidic compartments and so is absent from its mature endosomal form. Mutagenesis experiments demonstrated that the propeptide controls the assembly of the CD1e α-chain with β2-microglobulin, whereas propeptide-deleted CD1e molecules are immunologically active. Comparison of CD1e cDNAs from different mammalian species indicates that the CD1e propeptide is conserved during evolution, suggesting that it may also optimize the generation of CD1e molecules in other species.
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Tentori, L., G. Graziani, S. A. Porcelli, M. Sugita, M. B. Brenner, R. Madaio, E. Bonmassar, A. Giuliani, and A. Aquino. "Rifampin Increases Cytokine-Induced Expression of the CD1b Molecule in Human Peripheral Blood Monocytes." Antimicrobial Agents and Chemotherapy 42, no. 3 (March 1, 1998): 550–54. http://dx.doi.org/10.1128/aac.42.3.550.
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ABSTRACT In recent years, it has been shown that a nonclassical, major histocompatibility complex-independent system (i.e., CD1-restricted T-cell responses) is involved in T-cell immunity against nonpeptide antigens. The CD1 system appears to function by presenting microbial lipid antigens to specific T cells, and the antigens so far identified include several known constituents of mycobacterial cell walls. Among the four known human CD1 isoforms, the CD1b protein is the best characterized with regard to its antigen-presenting function. Expression of CD1b is upregulated on human blood monocytes upon exposure to granulocyte/macrophage-colony stimulating factor, alone or in combination with interleukin-4 (IL-4) (S. A. Porcelli, Adv. Immunol. 59:1–98, 1995). Rifampin (RFP) and its derivatives are widely used for chemoprophylaxis or chemotherapy against Mycobacterium tuberculosis. However, this agent was found to reduce the mitogen responsiveness of human B and T lymphocytes, chemotaxis, and delayed-type hypersensitivity. The present study extends the immunopharmacological profile of RFP by examining its effects on CD1b expression by human peripheral blood monocytes exposed to GM-CSF plus IL-4. The results showed that clinically attainable concentrations (i.e., 2 or 10 μg/ml for 24 h) of the agent produced a marked increase in CD1b expression on the plasma membrane, as evaluated by fluorescence-activated cell sorter analysis, whereas it had no effect on cytosolic fractions, as indicated by Western blot analysis. This was found to be the result of increased CD1b gene expression, as shown by Northern blot analysis of CD1b mRNA. These results suggest that RFP could be of potential value in augmenting the CD1b-restricted antigen recognition system, thereby enhancing protective cellular immunity to M. tuberculosis.
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Stenger, Steffen, Kayvan R. Niazi, and Robert L. Modlin. "Down-Regulation of CD1 on Antigen-Presenting Cells by Infection with Mycobacterium tuberculosis." Journal of Immunology 161, no. 7 (October 1, 1998): 3582–88. http://dx.doi.org/10.4049/jimmunol.161.7.3582.
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Abstract Intracellular pathogens have developed efficient evasion strategies to survive the defenses of the host immune system. In this study, we describe a new escape mechanism utilized by Mycobacterium tuberculosis that involves the down-regulation of the Ag-presenting molecule CD1 from the cell surface of CD1+ APCs. The loss of CD1 from the cell surface is associated with a complete inhibition of the ability of the infected cells to present Ag to CD1-restricted T cells. The down-regulation of Ag-presenting molecules on CD1+ APC by infection with M. tuberculosis is unique for CD1, since the expression of the classical Ag-presenting molecules MHC class I and MHC class II is not influenced. Our data show that efficient down-regulation of CD1 requires infection of the cells with live mycobacteria, since heat killing of the bacteria completely abrogates the effect. The observed down-regulation is not due to the secretion of cytokines or other host- or pathogen-derived factors. Investigation of upstream events responsible for the down-regulation of CD1 revealed that infection with live M. tuberculosis decreased the steady state CD1-mRNA levels. This study introduces a novel evasion mechanism of M. tuberculosis that could contribute to persistence of intracellular infection by avoiding immune recognition.
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Smed-Sörensen, Anna, Markus Moll, Tan-Yun Cheng, Karin Loré, Anna-Carin Norlin, Leif Perbeck, D. Branch Moody, Anna-Lena Spetz, and Johan K. Sandberg. "IgG regulates the CD1 expression profile and lipid antigen-presenting function in human dendritic cells via FcγRIIa." Blood 111, no. 10 (May 15, 2008): 5037–46. http://dx.doi.org/10.1182/blood-2007-07-099549.
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Abstract Dendritic cells (DCs) process and present bacterial and endogenous lipid antigens in complex with CD1 molecules to T cells and invariant natural killer T (NKT) cells. However, different types of DCs, such as blood myeloid DCs and skin Langerhans cells, exhibit distinct patterns of CD1a, CD1b, CD1c, and CD1d expression. The regulation of such differences is incompletely understood. Here, we initially observed that monocyte-derived DCs cultured in an immunoglobulin-rich milieu expressed CD1d but not CD1a, CD1b, and CD1c, whereas DCs cultured in the presence of low levels of immunoglobulins had an opposite CD1 profile. Based on this, we tested the possibility that immunoglobulins play a central role in determining these differences. IgG depletion and intravenous immunoglobulin (IVIg) add-in experiments strongly supported a role for IgG in directing the CD1 expression profile. Blocking experiments indicated that this effect was mediated by FcγRIIa (CD32a), and quantitative polymerase chain reaction data demonstrated that regulation of the CD1 profile occurred at the gene expression level. Finally, the ability of DCs to activate CD1-restricted NKT cells and T cells was determined by this regulatory effect of IgG. Our data demonstrate an important role for FcγRIIa in regulating the CD1 antigen presentation machinery of human DCs.
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Grant, Ethan P., Massimo Degano, Jean-Pierre Rosat, Steffen Stenger, Robert L. Modlin, Ian A. Wilson, Steven A. Porcelli, and Michael B. Brenner. "Molecular Recognition of Lipid Antigens by T Cell Receptors." Journal of Experimental Medicine 189, no. 1 (January 4, 1999): 195–205. http://dx.doi.org/10.1084/jem.189.1.195.
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The T cell antigen receptor (TCR) mediates recognition of peptide antigens bound in the groove of major histocompatibility complex (MHC) molecules. This dual recognition is mediated by the complementarity-determining residue (CDR) loops of the α and β chains of a single TCR which contact exposed residues of the peptide antigen and amino acids along the MHC α helices. The recent description of T cells that recognize hydrophobic microbial lipid antigens has challenged immunologists to explain, in molecular terms, the nature of this interaction. Structural studies on the murine CD1d1 molecule revealed an electrostatically neutral putative antigen-binding groove beneath the CD1 α helices. Here, we demonstrate that α/β TCRs, when transferred into TCR-deficient recipient cells, confer specificity for both the foreign lipid antigen and CD1 isoform. Sequence analysis of a panel of CD1-restricted, lipid-specific TCRs reveals the incorporation of template-independent N nucleotides that encode diverse sequences and frequent charged basic residues at the V(D)J junctions. These sequences permit a model for recognition in which the TCR CDR3 loops containing charged residues project between the CD1 α helices, contacting the lipid antigen hydrophilic head moieties as well as adjacent CD1 residues in a manner that explains antigen specificity and CD1 restriction.
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Blue, M. L., H. Levine, J. F. Daley, K. R. Branton, and S. F. Schlossman. "Expression of CD1 and class I MHC antigens by human thymocytes." Journal of Immunology 142, no. 8 (April 15, 1989): 2714–20. http://dx.doi.org/10.4049/jimmunol.142.8.2714.
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Abstract The acquisition of surface class I MHC molecules is associated with the maturation of thymocytes. Here, surface expression of class I MHC and CD1, which represents a family of MHC-related molecules, was analyzed on various human immature and mature thymocyte subpopulations. Class I expression was inversely related to the expression of CD1. The majority of CD4+ CD8+ cortical type thymocytes expressed low levels of class I MHC Ag, the previously described CD4+ CD8+ thymocyte subpopulation with low CD8 expression exhibited intermediate levels of class I MHC, whereas most of the single positive CD4 and CD8 thymocytes displayed high levels of class I MHC. Biochemical comparison of CD1 and class I showed that thymic class I molecules were post-translationally modified by phosphorylation, whereas CD1 was not phosphorylated. Furthermore, our studies suggested that in addition to CD1/CD8 complexes, thymocytes bear CD8/class I complexes. Chemical cross-linking and peptide mapping studies clearly identified the CD8-associated protein on thymic clones as the class I MHC molecule.
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Giuliani, Anna, Salvatore P. Prete, Grazia Graziani, Angelo Aquino, Alessandra Balduzzi, Masahiko Sugita, Michael B. Brenner, et al. "Influence of Mycobacterium bovisBacillus Calmette Guérin on In Vitro Induction of CD1 Molecules in Human Adherent Mononuclear Cells." Infection and Immunity 69, no. 12 (December 1, 2001): 7461–70. http://dx.doi.org/10.1128/iai.69.12.7461-7470.2001.
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ABSTRACT Nonpeptide antigens (including glycolipids of microbial origin) can be presented to T cells by CD1 molecules expressed on monocyte-derived dendritic cells. These HLA unrestricted responses appear to play a role in host immunity against Mycobacterium tuberculosis and other pathogenic bacteria. It is known that vaccination withMycobacterium bovis bacillus Calmette-Guérin (BCG) has limited efficacy in many clinical settings, although the reasons for its inadequacy remain unclear. Here we have investigated the influence of BCG on the induction of CD1b on human monocytes by granulocyte-macrophage colony-stimulating factor (GM-CSF), which is believed to be the principal inducer of this antigen-presenting molecule. Although BCG alone led to a slight induction of CD1b expression, this agent reduced markedly the ability of GM-CSF to induce high levels of CD1b that were typically observed in uninfected cells. Inhibition of CD1b expression in BCG-infected monocytes was apparent at both the mRNA transcript and CD1b protein levels. Down-regulation of CD1b expression by BCG was mediated, at least in part, by one or more soluble factors and could not be reversed with high concentrations of GM-CSF or a variety of other cytokines. The present results suggest that BCG could diminish the efficiency of CD1-restricted T-cell responses against nonpeptide mycobacterial antigens by reducing CD1 expression on antigen-presenting cells. These findings have potential implications for understanding the nature of the immune response elicited by BCG in humans and suggest potential strategies that could be important for the development of better vaccines for the prevention of tuberculosis.
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Shamshiev, A., H. J. Gober, A. Donda, Z. Mazorra, L. Mori, and G. De Libero. "Presentation of the Same Glycolipid by Different CD1 Molecules." Journal of Experimental Medicine 195, no. 8 (April 8, 2002): 1013–21. http://dx.doi.org/10.1084/jem.20011963.
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Five CD1 molecules are expressed in humans and it is unclear whether they have specialized or redundant functions. We found that sulfatide is a promiscuous CD1-binding ligand and have isolated T cell clones that are specific for sulfatide and restricted by distinct CD1 molecules. These clones have been used to compare the capacity of different CD1 to present the same glycolipid, to induce effector functions, and to form persistent immunogenic complexes. CD1a, CD1b, and CD1c molecules similarly load sulfatide on the cell surface without processing, and prime Th1 and Th2 responses. Stimulation by sulfatide-loaded CD1a persists much longer than that by CD1b and CD1c in living cells. Use of recombinant soluble CD1a confirmed the prolonged capacity to stimulate T cells. Moreover, other glycosphingolipids bind to all CD1, which suggests the presence of additional promiscuous ligands. Thus, group I CD1 molecules present an overlapping set of self-glycolipids, even though they are quite divergent from an evolutionary point of view.
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Xu, Chuanhui, Riemer de Vries, Lydia Visser, Arjan Diepstra, Stephan D. Gadola, Sibrand Poppema, and Anke Van Den Berg. "Expression of CD1c, CD1d and Presence of Invariant NKT Cells in Hodgkin Lymphoma." Blood 114, no. 22 (November 20, 2009): 3659. http://dx.doi.org/10.1182/blood.v114.22.3659.3659.
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Abstract Abstract 3659 Poster Board III-595 Introduction Hodgkin lymphoma (HL) is a B-cell neoplasm characterized by a minority of neoplastic cells, the so-called Hodgkin and Reed-Sternberg (HRS) cells. The HRS cells are located within an extensive infiltrate of reactive cells, including T cells, B cells, plasma cells, stromal cells, eosinophils and macrophages. CD1 molecules are non-classical MHC I-like molecules that present lipid antigens to T cells, triggering a specific immune response. Of the five CD1 isoforms (CD1a, CD1b, CD1c, CD1d and CD1e) expressed in human tissue, only CD1c and CD1d are expressed in B cells. The T cell receptors (TCRs) of T cells that recognize CD1c are indistinguishable from those that recognize MHC class I or II complexes. In contrast, CD1d presents lipid antigens to invariant Natural Killer T cells (iNKT cells), which are characterized by the expression of a semi-invariant Vα24Jα18 chain plus a limited set of β chains. CD4− and CD4+ iNKT cells were demonstrated as two distinct functional subsets in terms of cytokine production and cytotoxic activation. Immunoregulatory CD1 restricted T cells have been implicated in the pathogenesis of many cancers, but its role in HL is still unknown. In this study, we analyzed the expression of CD1c, CD1d and presence of iNKT cells in HL. Methods Expression of CD1c and CD1d was determined by immunocytochemistry in four HL cell lines KMH2, L1236, L428 and U-HO1. CD1c and CD1d expression in both HRS cells and reactive cells was studied in 46 HL patient tissues by immunohistochemistry. Cell suspensions of ten HL cases were studied for the presence of iNKT cells using monoclonal antibodies against human iNKT cell (clone 6B11) and TCR Vβ11 (clone C21) by flow cytometry. The percentage of CD4+ iNKT cells was determined in the gated iNKT cell population. Results Cytoplasmic CD1d expression was found in four HL cell lines and membranous CD1d expression was found in KMH2 and L1236. CD1c expression was negative in all four HL cell lines. CD1d expression was detected in HRS cells in 46% (21/46) of the HL cases. No correlation was observed between CD1d expression and presence of EBV in HRS cells. In contrast, CD1c expression was negative in HRS cells in all HL cases. Both CD1c and CD1d were detected in reactive cells in all HL cases albeit at varying frequencies. The mean percentage of CD1d restricted iNKT cells was 4% (range 0.8-8%) in HL cell suspensions irrespective of CD1d expression status in HRS cells. In reactive lymph node (RLN) the mean percentage of iNKT cells was also 4% (range 0.4-7%). Approximately half of the iNKT cells were CD4+ in both HL and RLN cell suspensions. Conclusion Expression of CD1d was found in four HL cell lines and in HRS cells of ∼50% of the HL cases. In HL cell suspensions, about 4% (range 0.8-8%) of the reactive background cells were iNKT cells. Disclosures: No relevant conflicts of interest to declare.
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Moody, D. Branch, and Sara Suliman. "CD1: From Molecules to Diseases." F1000Research 6 (October 30, 2017): 1909. http://dx.doi.org/10.12688/f1000research.12178.1.
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The human cluster of differentiation (CD)1 system for antigen display is comprised of four types of antigen-presenting molecules, each with a distinct functional niche: CD1a, CD1b, CD1c, and CD1d. Whereas CD1 proteins were thought solely to influence T-cell responses through display of amphipathic lipids, recent studies emphasize the role of direct contacts between the T-cell receptor and CD1 itself. Moving from molecules to diseases, new research approaches emphasize human CD1-transgenic mouse models and the study of human polyclonal T cells in vivo or ex vivo in disease states. Whereas the high genetic diversity of major histocompatibility complex (MHC)-encoded antigen-presenting molecules provides a major hurdle for designing antigens that activate T cells in all humans, the simple population genetics of the CD1 system offers the prospect of discovering or designing broadly acting immunomodulatory agents.
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Exley, Mark, Jorge Garcia, Steven P. Balk, and Steven Porcelli. "Requirements for CD1d Recognition by Human Invariant Vα24+ CD4−CD8− T Cells." Journal of Experimental Medicine 186, no. 1 (July 7, 1997): 109–20. http://dx.doi.org/10.1084/jem.186.1.109.
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A subset of human CD4−CD8− T cells that expresses an invariant Vα24-JαQ T cell receptor (TCR)-α chain, paired predominantly with Vβ11, has been identified. A series of these Vα24 Vβ11 clones were shown to have TCR-β CDR3 diversity and express the natural killer (NK) locus–encoded C-type lectins NKR-P1A, CD94, and CD69. However, in contrast to NK cells, they did not express killer inhibitory receptors, CD16, CD56, or CD57. All invariant Vα24+ clones recognized the MHC class I–like CD16 molecule and discriminated between CD1d and other closely related human CD1 proteins, indicating that recognition was TCR-mediated. Recognition was not dependent upon an endosomal targeting motif in the cytoplasmic tail of CD1d. Upon activation by anti-CD3 or CD1d, the clones produced both Th1 and Th2 cytokines. These results demonstrate that human invariant Vα24+ CD4−CD8− T cells, and presumably the homologous murine NK1+ T cell population, are CD1d reactive and functionally distinct from NK cells. The conservation of this cell population and of the CD1d ligand across species indicates an important immunological function.
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Adams, Erin J. "Diverse antigen presentation by the Group 1 CD1 molecule, CD1c." Molecular Immunology 55, no. 2 (September 2013): 182–85. http://dx.doi.org/10.1016/j.molimm.2012.10.019.
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Pereira, Catia S., and M. Fatima Macedo. "CD1-Restricted T Cells at the Crossroad of Innate and Adaptive Immunity." Journal of Immunology Research 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/2876275.
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Lipid-specific T cells comprise a group of T cells that recognize lipids bound to the MHC class I-like CD1 molecules. There are four isoforms of CD1 that are expressed at the surface of antigen presenting cells and therefore capable of presenting lipid antigens: CD1a, CD1b, CD1c, and CD1d. Each one of these isoforms has distinct structural features and cellular localizations, which promotes binding to a broad range of different types of lipids. Lipid antigens originate from either self-tissues or foreign sources, such as bacteria, fungus, or plants and their recognition by CD1-restricted T cells has important implications in infection but also in cancer and autoimmunity. In this review, we describe the characteristics of CD1 molecules and CD1-restricted lipid-specific T cells, highlighting the innate-like and adaptive-like features of different CD1-restricted T cell subtypes.
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Bagchi, Sreya, Hong Zhang, Ying He, and Chyung-Ru Wang. "Self-lipid specific T cells, restricted by CD1b, contribute to the development of hyperlipidemia-associated skin inflammation (BA11P.133)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 184.15. http://dx.doi.org/10.4049/jimmunol.194.supp.184.15.
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Abstract Psoriasis, a chronic inflammatory skin disease, is associated with hyperlipidemia. While conventional T cells usually exacerbate psoriasis, the role of self-lipid reactive CD1-restricted T cells requires further study. CD1 molecules present lipid antigens to T cells and are divided in to two groups. Group 1 includes CD1a, CD1b, CD1c while CD1d belongs to group 2. Humans express both group 1 and group 2 CD1 molecules whereas mice only have CD1d. Thus, due to the lack of a suitable animal model, the role of autoreactive group 1 CD1-restricted T cells in hyperlipidemia-associated inflammatory diseases is unknown. To overcome this challenge, our lab generated mice that expressed human CD1b and a CD1b-autoreactive T cell receptor (hCD1Tg/HJ1Tg). hCD1Tg/HJ1Tg mice were crossed to the ApoE-/- background to examine the role of CD1b-restricted T cells in hyperlipidemia (hCD1Tg/HJ1Tg/ApoE-/-). Interestingly, hCD1Tg/HJ1Tg/ApoE-/- mice developed severe psoriasis-like skin inflammation characterized by T cell and neutrophil infiltration along with a Th17-biased cytokine milieu. They also showed significantly increased polar lipid accumulation in the skin as compared to hCD1Tg/HJ1Tg/ApoE+ mice. This suggested that the presence of excessive lipids in the skin resulted in activation of CD1b-autoreacitve T cells, leading to the onset of skin pathology. This work demonstrates that autoreactive group 1 CD1-reactive T cells might serve as a link between inflammatory processes and hyperlipidemia.
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Gherardin, Nicholas A., Samuel J. Redmond, Hamish E. G. McWilliam, Catarina F. Almeida, Katherine H. A. Gourley, Rebecca Seneviratna, Shihan Li, et al. "CD36 family members are TCR-independent ligands for CD1 antigen–presenting molecules." Science Immunology 6, no. 60 (June 25, 2021): eabg4176. http://dx.doi.org/10.1126/sciimmunol.abg4176.
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CD1c presents lipid-based antigens to CD1c-restricted T cells, which are thought to be a major component of the human T cell pool. However, the study of CD1c-restricted T cells is hampered by the presence of an abundantly expressed, non–T cell receptor (TCR) ligand for CD1c on blood cells, confounding analysis of TCR-mediated CD1c tetramer staining. Here, we identified the CD36 family (CD36, SR-B1, and LIMP-2) as ligands for CD1c, CD1b, and CD1d proteins and showed that CD36 is the receptor responsible for non–TCR-mediated CD1c tetramer staining of blood cells. Moreover, CD36 blockade clarified tetramer-based identification of CD1c-restricted T cells and improved identification of CD1b- and CD1d-restricted T cells. We used this technique to characterize CD1c-restricted T cells ex vivo and showed diverse phenotypic features, TCR repertoire, and antigen-specific subsets. Accordingly, this work will enable further studies into the biology of CD1 and human CD1-restricted T cells.
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Matsunaga, Isamu, and Masahiko Sugita. "Mycoketide: A CD1c-Presented Antigen with Important Implications in Mycobacterial Infection." Clinical and Developmental Immunology 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/981821.
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Mycobacterium tuberculosisand related mycobacteria species are unique in that the acid-fast bacilli possess a highly lipid-rich cell wall that not simply confers resistance to treatment with acid alcohol, but also controls their survival and virulence. It has recently been established that a fraction of the cell wall lipid components of mycobacteria can function as antigens targeted by the acquired immunity of the host. Human group 1 CD1 molecules (CD1a, CD1b, and CD1c) bind a pool of lipid antigens expressed by mycobacteria and present them to specific T cells, thereby mediating an effective pathway for host defense against tuberculosis. The contrasting and mutually complementary functions of CD1a and CD1b molecules in terms of the repertoire of antigens they bind have been well appreciated, but it remains to be established how CD1c may play a unique role. Nevertheless, recent advances in our understanding of the CD1c structure as well as the biosynthetic pathway of a CD1c-presented antigen, mannose-1, β-phosphomycoketide, expressed by pathogenic mycobacteria now unravel a new aspect of the group 1 CD1 biology that has not been appreciated in previous studies of CD1a and CD1b molecules.
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Teitell, M., H. R. Holcombe, L. Brossay, A. Hagenbaugh, M. J. Jackson, L. Pond, S. P. Balk, C. Terhorst, P. A. Peterson, and M. Kronenberg. "Nonclassical behavior of the mouse CD1 class I-like molecule." Journal of Immunology 158, no. 5 (March 1, 1997): 2143–49. http://dx.doi.org/10.4049/jimmunol.158.5.2143.
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Abstract The mouse CD1 (mCD1) molecule is a class I-like molecule that is encoded outside of the MHC. We show here that mCD1 shares several properties with Ag-presenting class I molecules, including a requirement for beta2-microglobulin for stable cell-surface expression in T lymphocyte transfectants and thymocytes. mCD1 is also capable of binding to mouse CD8alphabeta heterodimers participating in the activation of CD8+ T cells in a manner similar to classical class I molecules. However, mCD1 surface expression is not decreased at high temperatures in cells that lack the transporter associated with Ag processing (TAP), including both RMA-S and Drosophila melanogaster cells. The data indicate that mCD1 does not require TAP to be expressed in a stable fashion at the cell surface. We speculate that the ability of mCD1 to reach the cell surface in transporter-deficient cells may reflect its ability to present a distinct set of ligands. The properties of mCD1 described here can account, in part, for the selection of the diverse populations of T cells that are known to be mCD1 reactive.
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Szatmari, Istvan, Attila Pap, Ralph Rühl, Jiang-Xing Ma, Petr A. Illarionov, Gurdyal S. Besra, Eva Rajnavolgyi, Balazs Dezso, and Laszlo Nagy. "PPARγ controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells." Journal of Experimental Medicine 203, no. 10 (September 18, 2006): 2351–62. http://dx.doi.org/10.1084/jem.20060141.
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Dendritic cells (DCs) expressing CD1d, a molecule responsible for lipid antigen presentation, are capable of enhancing natural killer T (iNKT) cell proliferation. The signals controlling CD1 expression and lipid antigen presentation are poorly defined. We have shown previously that stimulation of the lipid-activated transcription factor, peroxisome proliferator-activated receptor (PPAR)γ, indirectly regulates CD1d expression. Here we demonstrate that PPARγ, turns on retinoic acid synthesis by inducing the expression of retinol and retinal metabolizing enzymes such as retinol dehydrogenase 10 and retinaldehyde dehydrogenase type 2 (RALDH2). PPARγ-regulated expression of these enzymes leads to an increase in the intracellular generation of all-trans retinoic acid (ATRA) from retinol. ATRA regulates gene expression via the activation of the retinoic acid receptor (RAR)α in human DCs, and RARα acutely regulates CD1d expression. The retinoic acid–induced elevated expression of CD1d is coupled to enhanced iNKT cell activation. Furthermore, in vivo relevant lipids such as oxidized low-density lipoprotein can also elicit retinoid signaling leading to CD1d up-regulation. These data show that regulation of retinoid metabolism and signaling is part of the PPARγ-controlled transcriptional events in DCs. The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression.
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Borkowski, Andrew William, and Wendy L. Havran. "Epithelial and bone marrow derived sources of Cd1d contribute to wound repair." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 126.21. http://dx.doi.org/10.4049/jimmunol.196.supp.126.21.
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Abstract Wound healing is a multifaceted process that depends on both epithelial and bone marrow derived cells to promote proper healing. Recent publications have shown that a subset of T cells in the skin are activated by certain lipids bound to CD1 molecules. Cd1d, the isoform of CD1 expressed in mice, is an MHC-like molecule that binds lipid antigens and is expressed by Langerhans cells (LCs), macrophages, B cells, and wounded keratinocytes. As our lab has previously shown that T cell activation in the skin promotes wound healing, we hypothesize that Cd1d is an important component of normal wound healing. To investigate this hypothesis, we administered full thickness wounds to the dorsal skin of WT and Cd1d−/− mice and analyzed wound closure. Cd1d−/− mice had a significant delay in wound healing between days 1 and 5 compared to WT controls. Analysis of ex vivo wound healing failed to show any difference in wound closure rates between WT and Cd1d−/− skin. This suggested that an infiltrating cell type is at least partially responsible for the observed difference in in vivo wound healing. Transfer of WT bone marrow cells into lethally irradiated Cd1d−/− mice did not rescue the wound healing defect observed in Cd1d−/− mice. Interestingly, transfer of Cd1d−/− bone marrow into WT mice caused a delay in wound healing. Analysis of wounded skin demonstrated that significantly fewer macrophages and LCs were present in Cd1d−/− epidermis. We conclude that the Cd1d-mediated wound healing defect is dependent on both resident LCs and infiltrating macrophages, and continue to investigate how Cd1d expressed by LCs promotes wound repair as studies have shown that LCs have an immunosuppressive effect in models of contact hypersensitivity and UVB-induced inflammation.
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Shirin, Salma, Erwin Buncel, and Gary W. vanLoon. "The use of β-cyclodextrins to enhance the aqueous solubility of trichloroethylene and perchloroethylene and their removal from soil organic matter: Effect of substituents." Canadian Journal of Chemistry 81, no. 1 (January 1, 2003): 45–52. http://dx.doi.org/10.1139/v02-205.
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This paper describes a systematic study for the evaluation of different substituted β-cyclodextrins (β-CDs), as agents for the enhancement of the aqueous solubility of two major organic pollutants, trichloroethylene (TCE) and perchloroethylene (PCE). The aqueous solubility enhancement occurs through the formation of hostguest inclusion complexes between the CD molecule (host) and the polychloroethylene (guest) and is driven primarily by hydrophobic forces. The CDs evaluated are: methyl-β-CD (Mβ-CD), hydroxypropyl-β-CD (HPβ-CD), carboxymethyl-β-CD (CMβ-CD1, CMβ-CD2), and sulfated-β-CD (Sβ-CD1, Sβ-CD2); the degree of substitution was also varied. Using a 5% (w/v) aqueous CD solution, solubility enhancement factors (St/So) up to 5.5 and 14 were determined for TCE and PCE, respectively. Binding constants (K11) for TCE with the substituted CDs were evaluated using an 1H NMR technique; these were found to range from 3 to 120 M1. It was shown that solubility enhancement, as well as the binding constant, is dependent on the type and degree of substitution of the β-CD molecule; the determining factors are discussed. The CDs are also capable of effective removal of PCE and TCE retained by soil organic matter. Thus, a suitably substituted β-CD may be a valuable additive in pump-and-treat protocols for site remediation of polychlorinated organics. Key words: Cyclodextrin, trichloroethylene, perchloroethylene, solubility enhancement, binding constant, soil and water remediation.
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Kansas, GS, MJ Muirhead, and MO Dailey. "Expression of the CD11/CD18, leukocyte adhesion molecule 1, and CD44 adhesion molecules during normal myeloid and erythroid differentiation in humans." Blood 76, no. 12 (December 15, 1990): 2483–92. http://dx.doi.org/10.1182/blood.v76.12.2483.2483.
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Abstract We have used three-color flow cytometry to investigate the pattern of expression of the CD11/CD18, CD44, and leukocyte adhesion molecule 1 (LAM-1) adhesion molecules during myeloid and erythroid differentiation in humans. The earliest myeloid cells, identified as CD33loCD15-, were exclusively CD44hi but contained both leukocyte function-associated antigen 1 (LFA-1hi) and LFA-1lo cells, as well as LAM-1+ and LAM-1- cells. This CD33loCD15- myeloid subpopulation expressed only low levels of CD11c and failed to express CD11b, CD14, or any lymphoid (CD3, CD16, CD19) antigens or glycophorin. Commitment to monocyte differentiation, suggested by the presence of an LFA-1hi CD11c+ subset within the CD33loCD15- subpopulation, was clearly signaled by upregulation of CD33; these monocyte-lineage committed cells were exclusively CD33hi, CD44hi, CD11ahi, CD11c+, and exhibited a broad range of intensity of CD15 expression. Later stages of monopoiesis were identified by acquisition of CD11b, and subsequently of CD14. Myeloid cells committed to granulopoiesis remained LFA-1lo, and underwent a sharp upregulation of CD15 along with downregulation of both CD33 and CD44. Successive stages of granulocyte development were marked by expression of CD11b and, subsequently, of CD16. The earliest cells capable of erythroid differentiation were CD44hi, LFA-1lo, and LAM-1+. Both LFA-1 and LAM-1 were lost before the onset of glycophorin (glyco) expression, whereas CD44 expression remained high on glyco+ cells, which also expressed CD45. CD44 expression was intermediate on glyco+ CD71+ cells, and low on glyco+ CD45- CD71- cells, similar to normal, circulating erythrocytes. Our results allow us to phenotypically define discrete stages in the normal development of monocytes, neutrophils, and erythrocytes. The expression of LFA-1, LAM-1, and high levels of CD44 on the most primitive hematopoietic cells detectable by flow cytometry suggests that at least some of these molecules are critically involved in leukocyte adhesion during development.
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Kansas, GS, MJ Muirhead, and MO Dailey. "Expression of the CD11/CD18, leukocyte adhesion molecule 1, and CD44 adhesion molecules during normal myeloid and erythroid differentiation in humans." Blood 76, no. 12 (December 15, 1990): 2483–92. http://dx.doi.org/10.1182/blood.v76.12.2483.bloodjournal76122483.
Full textAbstract:
We have used three-color flow cytometry to investigate the pattern of expression of the CD11/CD18, CD44, and leukocyte adhesion molecule 1 (LAM-1) adhesion molecules during myeloid and erythroid differentiation in humans. The earliest myeloid cells, identified as CD33loCD15-, were exclusively CD44hi but contained both leukocyte function-associated antigen 1 (LFA-1hi) and LFA-1lo cells, as well as LAM-1+ and LAM-1- cells. This CD33loCD15- myeloid subpopulation expressed only low levels of CD11c and failed to express CD11b, CD14, or any lymphoid (CD3, CD16, CD19) antigens or glycophorin. Commitment to monocyte differentiation, suggested by the presence of an LFA-1hi CD11c+ subset within the CD33loCD15- subpopulation, was clearly signaled by upregulation of CD33; these monocyte-lineage committed cells were exclusively CD33hi, CD44hi, CD11ahi, CD11c+, and exhibited a broad range of intensity of CD15 expression. Later stages of monopoiesis were identified by acquisition of CD11b, and subsequently of CD14. Myeloid cells committed to granulopoiesis remained LFA-1lo, and underwent a sharp upregulation of CD15 along with downregulation of both CD33 and CD44. Successive stages of granulocyte development were marked by expression of CD11b and, subsequently, of CD16. The earliest cells capable of erythroid differentiation were CD44hi, LFA-1lo, and LAM-1+. Both LFA-1 and LAM-1 were lost before the onset of glycophorin (glyco) expression, whereas CD44 expression remained high on glyco+ cells, which also expressed CD45. CD44 expression was intermediate on glyco+ CD71+ cells, and low on glyco+ CD45- CD71- cells, similar to normal, circulating erythrocytes. Our results allow us to phenotypically define discrete stages in the normal development of monocytes, neutrophils, and erythrocytes. The expression of LFA-1, LAM-1, and high levels of CD44 on the most primitive hematopoietic cells detectable by flow cytometry suggests that at least some of these molecules are critically involved in leukocyte adhesion during development.
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Angénieux, Catherine, J. Salamero, Dominique Fricker, Jean-Pierre Cazenave, Bruno Goud, Daniel Hanau, and Henri de la Salle. "Characterization of CD1e, a Third Type of CD1 Molecule Expressed in Dendritic Cells." Journal of Biological Chemistry 275, no. 48 (August 17, 2000): 37757–64. http://dx.doi.org/10.1074/jbc.m007082200.
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Li, Fenfang, Miaoli Zhu, and Liping Lu. "A two-dimensional cadmium(II) coordination polymer constructed from 4-carboxy-1-(4-carboxylatobenzyl)-2-propyl-1H-imidazole-5-carboxylate and 1-(4-carboxylatobenzyl)-2-propyl-1H-imidazole-4-carboxylate ligands." Acta Crystallographica Section C Structural Chemistry 74, no. 8 (July 24, 2018): 967–73. http://dx.doi.org/10.1107/s2053229618010239.
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Crystals of poly[[aqua[μ3-4-carboxy-1-(4-carboxylatobenzyl)-2-propyl-1H-imidazole-5-carboxylato-κ5 O 1 O 1′:N 3,O 4:O 5][μ4-1-(4-carboxylatobenzyl)-2-propyl-1H-imidazole-4-carboxylato-κ7 N 3,O 4:O 4,O 4′:O 1,O 1′:O 1]cadmium(II)] monohydrate], {[Cd2(C15H14N2O4)(C16H14N2O6)(H2O)]·H2O} n or {[Cd2(Hcpimda)(cpima)(H2O)]·H2O} n , (I), were obtained from 1-(4-carboxybenzyl)-2-propyl-1H-imidazole-4,5-dicarboxylic acid (H3cpimda) and cadmium(II) chloride under hydrothermal conditions. The structure indicates that in-situ decarboxylation of H3cpimda occurred during the synthesis process. The asymmetric unit consists of two Cd2+ centres, one 4-carboxy-1-(4-carboxylatobenzyl)-2-propyl-1H-imidazole-5-carboxylate (Hcpimda2−) anion, one 1-(4-carboxylatobenzyl)-2-propyl-1H-imidazole-4-carboxylate (cpima2−) anion, one coordinated water molecule and one lattice water molecule. One Cd2+ centre, i.e. Cd1, is hexacoordinated and displays a slightly distorted octahedral CdN2O4 geometry. The other Cd centre, i.e. Cd2, is coordinated by seven O atoms originating from one Hcpimda2− ligand and three cpima2− ligands. This Cd2+ centre can be described as having a distorted capped octahedral coordination geometry. Two carboxylate groups of the benzoate moieties of two cpima2− ligands bridge between Cd2 centres to generate [Cd2O2] units, which are further linked by two cpima2− ligands to produce one-dimensional (1D) infinite chains based around large 26-membered rings. Meanwhile, adjacent Cd1 centres are linked by Hcpimda2− ligands to generate 1D zigzag chains. The two types of chains are linked through a μ2-η2 bidentate bridging mode from an O atom of an imidazole carboxylate unit of cpima2− to give a two-dimensional (2D) coordination polymer. The simplified 2D net structure can be described as a 3,6-coordinated net which has a (43)2(46.66.83) topology. Furthermore, the FT–IR spectroscopic properties, photoluminescence properties, powder X-ray diffraction (PXRD) pattern and thermogravimetric behaviour of the polymer have been investigated.
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Small, T. N., R. W. Knowles, C. Keever, N. A. Kernan, N. Collins, R. J. O'Reilly, B. Dupont, and N. Flomenberg. "M241 (CD1) expression on B lymphocytes." Journal of Immunology 138, no. 9 (May 1, 1987): 2864–68. http://dx.doi.org/10.4049/jimmunol.138.9.2864.
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Abstract The human thymus leukemia-like antigens (CD1a-c) consist of three similar glycoproteins found on subpopulations of normal thymocytes, T cell acute leukemias, and cutaneous dendritic cells. The CD1c antigen recognized by the M241 monoclonal antibody was detected on the circulating mononuclear cells of three children with severe combined immunodeficiency disease (SCID). Two-color immunofluorescence analysis demonstrated that M241 expression (43 to 95%) was limited to cells expressing the B cell-restricted antigens B4 (CD19), B1 (CD20), and surface immunoglobulin. To confirm M241 expression on normal cells of the B lineage rather than aberrant expression limited to SCID B cells, its expression was demonstrated serologically and biochemically on purified B cells from spleen, tonsil, and peripheral blood. Parallel analyses with monoclonal antibodies NA1/34 and 4A76 demonstrated that the CD1a and CD1b molecules were negative on all B cells that were studied. It has been hypothesized that the CD1 molecules represent the human counterpart of the murine thymus leukemia antigens due to their similar size, limited tissue distribution, and association with beta 2-microglobulin. This study suggests that a subset of CD1 antigens detected by M241 (CD1c) may represent a human analog of a murine Qa antigen due to its extended distribution on normal peripheral B cells.
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Uckun, FM, A. Muraguchi, JA Ledbetter, T. Kishimoto, RT O'Brien, JS Roloff, K. Gajl- Peczalska, A. Provisor, and B. Koller. "Biphenotypic leukemic lymphocyte precursors in CD2+CD19+ acute lymphoblastic leukemia and their putative normal counterparts in human fetal hematopoietic tissues." Blood 73, no. 4 (March 1, 1989): 1000–1015. http://dx.doi.org/10.1182/blood.v73.4.1000.1000.
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Abstract During detailed immunophenotypic analyses of marrow blasts from 336 acute lymphoblastic leukemia (ALL) patients, a very small percentage of cases reactive with B-cell-directed as well as T-cell-directed monoclonal antibodies (MoAbs) were identified. Five ALL cases were biphenotypic since they coexpressed CD2 (Tp50) and CD19 (Bp95) antigens at the single-cell level. The composite immunophenotype of these biphenotypic ALL cases was [TdT+HLA-ABC+CD2+CD3-CD10+CD13-CD14-CD16- CD19+CD20+ ++-CD21-CD33-CD34+Bgp95-C mu- slg-]. Low-molecular-weight B- cell growth factor (LMW-BCGF), recombinant interleukin-2 (rIL-2), and rIL-3 stimulated the proliferative activity of biphenotypic leukemic lymphocyte precursors without inducing differentiation. In the presence of the phorbol ester TPA, leukemic blasts from two cases differentiated along the B precursor pathway to the [CD2-CD10+CD19+CD20+C mu+slg-] pre- B cell stage. Biphenotypic ALL cases did not share a common configuration and gene rearrangement pattern of the immunoglobulin heavy chain genes or T-cell receptor (TCR) genes. Three cases had rearranged C mu genes but germline TCR genes, one case showed rearrangement of both C mu and TCR genes, and the remaining case had rearranged TCR genes but germline C mu genes. All five patients attained prompt remission after standard induction chemotherapy. Three to four years after initial diagnosis, four patients are now off chemotherapy and remain alive in their first remission. One patient relapsed at 3 years, 7 months, but promptly achieved complete remission after reinduction chemotherapy and remains in second remission off chemotherapy greater than 3 years after her reinduction therapy. With two-color immunofluorescence staining techniques and multiparameter flow cytometric analyses, we identified a small population of CD2+CD19+ lymphoid cells in fetal livers (FLs) and fetal bone marrows (FBMs), which may represent the putative normal counterparts of biphenotypic ALL blasts. A CD2+CD19+ normal biphenotypic lymphoid precursor cell line, designated FL 8.2 CD2+, was established from an FL of 8-weeks of gestational age by Epstein-Barr virus (EBV)-induced blastoid transformation. The composite immunophenotype of FL 8.2 CD2+ cell line was [TdT+HLA-ABC+HLA-DR+ CD2+CD5-CD7-CD10+/-CD13-CD19+CD20-CD21+ CD22+CD33-CD34+/-Bgp95-CDw40+C mu-slgD-slgM-]. FL 8.2 CD2+ cells showed germline patterns of immunoglobulin heavy-chain joining region, heavy- chain constant region, kappa light-chain constant region genes, and TCR beta-chain genes. Cross-linking of CD2 as well as CD19 antigens on FL 8.2 CD2+ cells caused an increase of intracellular ionized calcium.(ABSTRACT TRUNCATED AT 400 WORDS)
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Uckun, FM, A. Muraguchi, JA Ledbetter, T. Kishimoto, RT O'Brien, JS Roloff, K. Gajl- Peczalska, A. Provisor, and B. Koller. "Biphenotypic leukemic lymphocyte precursors in CD2+CD19+ acute lymphoblastic leukemia and their putative normal counterparts in human fetal hematopoietic tissues." Blood 73, no. 4 (March 1, 1989): 1000–1015. http://dx.doi.org/10.1182/blood.v73.4.1000.bloodjournal7341000.
Full textAbstract:
During detailed immunophenotypic analyses of marrow blasts from 336 acute lymphoblastic leukemia (ALL) patients, a very small percentage of cases reactive with B-cell-directed as well as T-cell-directed monoclonal antibodies (MoAbs) were identified. Five ALL cases were biphenotypic since they coexpressed CD2 (Tp50) and CD19 (Bp95) antigens at the single-cell level. The composite immunophenotype of these biphenotypic ALL cases was [TdT+HLA-ABC+CD2+CD3-CD10+CD13-CD14-CD16- CD19+CD20+ ++-CD21-CD33-CD34+Bgp95-C mu- slg-]. Low-molecular-weight B- cell growth factor (LMW-BCGF), recombinant interleukin-2 (rIL-2), and rIL-3 stimulated the proliferative activity of biphenotypic leukemic lymphocyte precursors without inducing differentiation. In the presence of the phorbol ester TPA, leukemic blasts from two cases differentiated along the B precursor pathway to the [CD2-CD10+CD19+CD20+C mu+slg-] pre- B cell stage. Biphenotypic ALL cases did not share a common configuration and gene rearrangement pattern of the immunoglobulin heavy chain genes or T-cell receptor (TCR) genes. Three cases had rearranged C mu genes but germline TCR genes, one case showed rearrangement of both C mu and TCR genes, and the remaining case had rearranged TCR genes but germline C mu genes. All five patients attained prompt remission after standard induction chemotherapy. Three to four years after initial diagnosis, four patients are now off chemotherapy and remain alive in their first remission. One patient relapsed at 3 years, 7 months, but promptly achieved complete remission after reinduction chemotherapy and remains in second remission off chemotherapy greater than 3 years after her reinduction therapy. With two-color immunofluorescence staining techniques and multiparameter flow cytometric analyses, we identified a small population of CD2+CD19+ lymphoid cells in fetal livers (FLs) and fetal bone marrows (FBMs), which may represent the putative normal counterparts of biphenotypic ALL blasts. A CD2+CD19+ normal biphenotypic lymphoid precursor cell line, designated FL 8.2 CD2+, was established from an FL of 8-weeks of gestational age by Epstein-Barr virus (EBV)-induced blastoid transformation. The composite immunophenotype of FL 8.2 CD2+ cell line was [TdT+HLA-ABC+HLA-DR+ CD2+CD5-CD7-CD10+/-CD13-CD19+CD20-CD21+ CD22+CD33-CD34+/-Bgp95-CDw40+C mu-slgD-slgM-]. FL 8.2 CD2+ cells showed germline patterns of immunoglobulin heavy-chain joining region, heavy- chain constant region, kappa light-chain constant region genes, and TCR beta-chain genes. Cross-linking of CD2 as well as CD19 antigens on FL 8.2 CD2+ cells caused an increase of intracellular ionized calcium.(ABSTRACT TRUNCATED AT 400 WORDS)
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Huber, S. A., D. Sartini, and M. Exley. "Vγ4+ T Cells Promote Autoimmune CD8+ Cytolytic T-Lymphocyte Activation in Coxsackievirus B3-Induced Myocarditis in Mice: Role for CD4+ Th1 Cells." Journal of Virology 76, no. 21 (November 1, 2002): 10785–90. http://dx.doi.org/10.1128/jvi.76.21.10785-10790.2002.
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ABSTRACT T cells expressing the Vγ4 T-cell receptor (TCR) promote myocarditis in coxsackievirus B3 (CVB3)-infected BALB/c mice. CD1, a major histocompatibility complex (MHC) class I-like molecule, is required for activation of Vγ4+ cells. Once activated, Vγ4+ cells initiate myocarditis through gamma interferon (IFN-γ)-mediated induction of CD4+ T helper type 1 (Th1) cells in the infected animal. These CD4+ Th1 cells are required for activation of an autoimmune CD8+ αβ TCR+ effector, which is the predominant pathogenic agent in this model of CVB3-induced myocarditis. Activated Vγ4+ cells can adoptively transfer myocarditis into BALB/c mice infected with a nonmyocarditic variant of CVB3 (H310A1) but cannot transfer myocarditis into either uninfected or CD1−/− recipients, demonstrating the need for both infection and CD1 expression for Vγ4+ cell function. In contrast, CD8+ αβ TCR+ cells transfer myocarditis into either infected CD1−/− or uninfected recipients, showing that once activated, the CD8+ αβ TCR+ effectors function independently of both virus and CD1. Vγ4+ cells given to mice lacking CD4+ T cells minimally activate the CD8+ αβ TCR+ cells. These studies show that Vγ4+ cells determine CVB3 pathogenicity by their ability to influence both the CD4+ and CD8+ adaptive immune response. Vγ4+ cells enhance CD4+ Th1 (IFN-γ+) cell activation through IFN-γ- and CD1-dependent mechanisms. CD4+ Th1 cells promote activation of the autoimmune CD8+ αβ TCR+ effectors.
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Jahng, Alex W., Igor Maricic, Brian Pedersen, Nicolas Burdin, Olga Naidenko, Mitchell Kronenberg, Yasuhiko Koezuka, and Vipin Kumar. "Activation of Natural Killer T Cells Potentiates or Prevents Experimental Autoimmune Encephalomyelitis." Journal of Experimental Medicine 194, no. 12 (December 17, 2001): 1789–99. http://dx.doi.org/10.1084/jem.194.12.1789.
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Natural killer (NK) T cells recognize lipid antigens in the context of the major histocompatibility complex (MHC) class 1–like molecule CD1 and rapidly secrete large amounts of the cytokines interferon (IFN)-γ and interleukin (IL)-4 upon T cell receptor (TCR) engagement. We have asked whether NK T cell activation influences adaptive T cell responses to myelin antigens and their ability to cause experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. While simultaneous activation of NK T cells with the glycolipid α-galactosylceramide (α-GalCer) and myelin-reactive T cells potentiates EAE in B10.PL mice, prior activation of NK T cells protects against disease. Exacerbation of EAE is mediated by an enhanced T helper type 1 (Th1) response to myelin basic protein and is lost in mice deficient in IFN-γ. Protection is mediated by immune deviation of the anti-myelin basic protein (MBP) response and is dependent upon the secretion of IL-4. The modulatory effect of α-GalCer requires the CD1d antigen presentation pathway and is dependent upon the nature of the NK T cell response in B10.PL or C57BL/6 mice. Because CD1 molecules are nonpolymorphic and remarkably conserved among different species, modulation of NK T cell activation represents a target for intervention in T cell–mediated autoimmune diseases.
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Wageh, S., and M. H. Badr. "Cd1−xZnxS nanoparticles stabilized by a bifunctional organic molecule." Physica E: Low-dimensional Systems and Nanostructures 40, no. 8 (June 2008): 2810–13. http://dx.doi.org/10.1016/j.physe.2007.12.013.
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Van Rhijn, Ildiko, Dale I. Godfrey, Jamie Rossjohn, and D. Branch Moody. "Lipid and small-molecule display by CD1 and MR1." Nature Reviews Immunology 15, no. 10 (September 21, 2015): 643–54. http://dx.doi.org/10.1038/nri3889.
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Park, Se-Ho, Delphine Guy-Grand, François A. Lemonnier, Chyung-Ru Wang, Albert Bendelac, and Bana Jabri. "Selection and Expansion of CD8α/α1 T Cell Receptor α/β1 Intestinal Intraepithelial Lymphocytes in the Absence of Both Classical Major Histocompatibility Complex Class I and Nonclassical Cd1 Molecules." Journal of Experimental Medicine 190, no. 6 (September 20, 1999): 885–90. http://dx.doi.org/10.1084/jem.190.6.885.
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Intestinal intraepithelial lymphocytes (IELs) in mice include two main subsets of TCR-α/β1 cells which differ functionally and ontogenically from each other. One expresses the CD8α/α homodimer, whereas the other expresses the CD8α/β heterodimer. Although the presence of all CD8+TCR-α/β1 IELs is dependent on β2-microglobulin molecules, the nature of the major histocompatibility complex (MHC) class I molecules recognized by the CD8α/α and the CD8α/β1 subsets has remained elusive. Using mutant mice lacking the expression of both H2-Kb and H2-Db, we show that the CD8α/β1TCR-α/β1 subset is dependent on K or D molecules, whereas the CD8α/α1TCR-α/β1 subset is independent of classical MHC class I molecules. Furthermore, the CD8α/α1 cells are conserved in mice lacking expression of CD1, a nonclassical MHC class I–like molecule previously proposed to be a potential ligand for IELs. Using transporter associated with antigen processing (TAP)-deficient mice, this cell population can be further separated into a TAP-dependent and a TAP-independent subset, suggesting either the recognition of two nonclassical MHC-like molecules, only one of which is TAP dependent, or the involvement of a single nonclassical MHC-like molecule that is only partially TAP dependent. These findings demonstrate that CD8α/β1TCR-α/β1 IELs are restricted by H-2K and H-2D molecules, whereas the unusual subset of CD8α/α1TCR-α/β1 resident IELs recognize nonclassical MHC class I–like molecules that are distinct from CD1.