scholarly journals Human P-selectin Glycoprotein Ligand-1 (PSGL-1) Interacts with the Skin-associated Chemokine CCL27 via Sulfated Tyrosines at the PSGL-1 Amino Terminus

2004 ◽  
Vol 279 (50) ◽  
pp. 51775-51782 ◽  
Author(s):  
Takako Hirata ◽  
Yuko Furukawa ◽  
Bo-Gie Yang ◽  
Kunio Hieshima ◽  
Minoru Fukuda ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Critical Role ◽  
Soluble Form ◽  
Amino Terminus ◽  
Leukocyte Rolling ◽  
Normal Medium ◽  
Skin Homing ◽  
Selectin Ligand

P-selectin glycoprotein ligand-1 (PSGL-1), a sialomucin expressed on leukocytes, is a major ligand for P-selectin and mediates leukocyte rolling on the endothelium. Here we show that human PSGL-1 interacts with CCL27 (CTACK/ILC/ESkine), a skin-associated chemokine that attracts skin-homing T lymphocytes. A recombinant soluble form of PSGL-1 (rPSGL-Ig) preferentially bound CCL27 among several chemokines tested. This interaction was abrogated by arylsulfatase treatment of rPSGL-Ig, suggesting that sulfated tyrosines play a critical role. In contrast, removal of eitherN-glycans orO-glycans by glycosidase treatment of rPSGL-Ig did not affect the interaction. The binding of CCL27 to a recombinant PSGL-1 synthesized in the presence of a sulfation inhibitor was lower than that produced in normal medium. Moreover, mutation of the tyrosines at the amino terminus of PSGL-1 to phenylalanine abolished the binding, further supporting the role of sulfated tyrosines in the CCL27-PSGL-1 interaction. Functionally, rPSGL-Ig reduced the chemotaxis of L1.2 cells expressing CCR10, the receptor for CCL27. In addition, the expression of human PSGL-1 on CCR10-expressing L1.2 cells resulted in reduced chemotaxis to CCL27. These findings suggest a role for PSGL-1 in regulating chemokine-mediated responses, in addition to its role as a selectin ligand.

scholarly journals Functional human IgA targets a conserved site on malaria sporozoites

2021 ◽  
Vol 13 (599) ◽  
pp. eabg2344
Author(s):  
Joshua Tan ◽  
Hyeseon Cho ◽  
Tossapol Pholcharee ◽  
Lais S. Pereira ◽  
Safiatou Doumbo ◽  
...  
Keyword(s):  
Critical Role ◽  
Parasite Burden ◽  
Circumsporozoite Protein ◽  
Amino Terminus ◽  
Endemic Region ◽  
Serum Iga ◽  
Iga Response ◽  
Functional Antibodies ◽  
Mucosal Pathogens

Immunoglobulin (Ig)A antibodies play a critical role in protection against mucosal pathogens. However, the role of serum IgA in immunity to nonmucosal pathogens, such as Plasmodium falciparum, is poorly characterized, despite being the second most abundant isotype in blood after IgG. Here, we investigated the circulating IgA response in humans to P. falciparum sporozoites that are injected into the skin by mosquitoes and migrate to the liver via the bloodstream to initiate malaria infection. We found that circulating IgA was induced in three independent sporozoite-exposed cohorts: individuals living in an endemic region in Mali, malaria-naïve individuals immunized intravenously with three large doses of irradiated sporozoites, and malaria-naïve individuals exposed to a single controlled mosquito bite infection. Mechanistically, we found evidence in an animal model that IgA responses were induced by sporozoites at dermal inoculation sites. From malaria-resistant individuals, we isolated several IgA monoclonal antibodies that reduced liver parasite burden in mice. One antibody, MAD2-6, bound to a conserved epitope in the amino terminus of the P. falciparum circumsporozoite protein, the dominant protein on the sporozoite surface. Crystal structures of this antibody revealed a unique mode of binding whereby two Fabs simultaneously bound either side of the target peptide. This study reveals a role for circulating IgA in malaria and identifies the amino terminus of the circumsporozoite protein as a target of functional antibodies.

scholarly journals Preexisting Virus-Specific T Lymphocytes-Mediated Enhancement of Adenovirus Infections to Human Blood CD14+ Cells

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 154
Author(s):  
Fengling Feng ◽  
Jin Zhao ◽  
Pingchao Li ◽  
Ruiting Li ◽  
Ling Chen ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Viral Infection ◽  
Viral Infections ◽  
Critical Role ◽  
Scavenger Receptor ◽  
Activation Markers ◽  
Gm Csf ◽  
Cell Responses ◽  
Underlying Mechanisms

Antigen-specific T lymphocytes play a critical role in controlling viral infections. However, we report here that preexisting virus-specific T cell responses also contribute to promoting adenovirus (Ad) infection. Previously, we found that CD14+ monocytes from Ad-seropositive individuals exhibited an increased susceptibility to Ad infection, when compared with that of Ad-seronegative individuals. But the underlying mechanisms for this enhancement of viral infection are not completely clarified. In this study, we found that the efficacy of Ad infection into CD14+ monocytes was significantly decreased after CD3+ T lymphocytes depletion from PBMC samples of Ad-seropositive individuals. In contrast, adding virus-specific CD3+ T lymphocytes into PBMC samples of Ad-seronegative individuals resulted in a significant increase of infection efficacy. CD3+ T lymphocytes in PBMC samples from Ad-seropositive individuals were more sensitive to be activated by adenovirus stimulus, characterized by upregulation of multiple cytokines and activation markers and also enhancement of cell proliferation. Further studies demonstrated that GM-CSF and IL-4 can promote Ad infection by up-regulating the expression of scavenger receptor 1 (SR-A) and integrins αVβ5 receptor of CD14+ cells. And taken together, these results suggest a novel role of virus-specific T cells in mediating enhancement of viral infection, and provide insights to understand the pathogenesis and complicated interactions between viruses and host immune cells.

Glycosylation-dependent inhibition of cutaneous lymphocyte–associated antigen expression: implications in modulating lymphocyte migration to skin

Blood ◽  
2003 ◽  
Vol 101 (2) ◽  
pp. 602-610 ◽  
Author(s):  
Charles J. Dimitroff ◽  
Ralph J. Bernacki ◽  
Robert Sackstein
Keyword(s):  
T Cells ◽  
Human Skin ◽  
Critical Role ◽  
Metabolic Inhibitors ◽  
Lymphocyte Migration ◽  
Skin Homing ◽  
Selectin Ligand ◽  
Adhesive Interactions ◽  
Selectin Binding ◽  
Ligand Activity

Constitutive E-selectin expression on dermal microvascular endothelial cells plays a critical role in mediating rolling adhesive interactions of human skin–homing T cells and in pathologic accumulation of lymphocytes in skin. The major E-selectin ligand on human skin–homing T cells is cutaneous lymphocyte–associated antigen (CLA), a specialized glycoform of P-selectin glycoprotein ligand-1 (PSGL-1) defined by monoclonal antibody HECA-452. Since HECA-452 reactivity, and not PSGL-1 polypeptide itself, confers the specificity of human T cells to enter dermal tissue, inhibition of HECA-452 expression is a potential strategy for modulating lymphocyte migration to skin. In this study, we examined the efficacy of several well-characterized metabolic inhibitors of glycosylation and of a novel fluorinated analog of N-acetylglucosamine (2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoro-D-glucopyranose [4-F-GlcNAc]) to alter HECA-452 expression on human CLA+ T cells and prevent cell tethering and rolling on selectins under shear stress. At concentrations that did not affect PSGL-1 expression, we found that swainsonine (inhibitor of complex-typeN-glycan synthesis) had no effect on HECA-452 expression or selectin ligand activity, whereas benzyl-O-N-acetylgalactosamide (BAG; inhibitor of O-glycan biosynthesis) ablated HECA-452 expression on PSGL-1 and significantly lowered selectin ligand activity. We found that 4-F-GlcNAc (putative inhibitor of poly-N-acetyllactosamine biosynthesis) was more potent than BAG at lowering HECA-452 expression and selectin binding. In addition, we show that 4-F-GlcNAc was directly incorporated into native CLA expressed on T cells, indicating direct inhibition on poly-N-acetyllactosamine elongation and selectin-binding determinants on PSGL-1 O-glycans. These observations establish a potential treatment approach for targeting pathologic lymphocyte trafficking to skin and indicate that 4-F-GlcNAc may be a promising agent for treatment of dermal tropism associated with malignancies and inflammatory disorders.

scholarly journals The Spacing between Cysteines Two and Three of the LDL-A Module of Tva Is Important for Subgroup A Avian Sarcoma and Leukosis Virus Entry

2004 ◽  
Vol 78 (2) ◽  
pp. 683-691 ◽  
Author(s):  
Tia Rai ◽  
Deborah Marble ◽  
Kayla Rihani ◽  
Lijun Rong
Keyword(s):  
Viral Entry ◽  
Critical Role ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Chimeric Protein ◽  
Amino Terminus ◽  
Viral Glycoprotein ◽  
Interaction Domain ◽  
Avian Sarcoma

ABSTRACT Rong et al. have demonstrated previously that with a few substitutions, the fourth repeat of human low-density lipoprotein (hLDL-A4) receptor can functionally replace the LDL-A module of Tva, the cellular receptor for subgroup A avian sarcoma and leukosis virus (ASLV-A), in viral entry (L. Rong, K. Gendron, and P. Bates, Proc. Natl. Acad. Sci. USA 95:8467-8472, 1998). Here we have shown that swapping the amino terminus of hLDL repeat 5 (hLDL-A5) with that of Tva, in addition to the corresponding substitutions made in human LDL-A4, was required to convert hLDL-A5 into an efficient ASLV-A receptor. These results substantiated our previous findings regarding the role of the specific residues in the viral interaction domain of Tva and demonstrated the critical role of the amino terminus of the Tva LDL-A module in ASLV-A infection. Furthermore, we have shown that the residues between cysteines 2 and 3 of the Tva LDL-A module in a Tva/LDL-A5 chimeric protein can be functionally replaced by the corresponding region of another LDL-A module, human LDL receptor-related protein repeat 22 (LDL-A22), to mediate efficient ASLV-A entry. Since the only conserved feature between the C2-C3 region of LDL-A22 and the Tva LDL-A module is that both contain nine amino acids of which none are conserved, we conclude that the spacing between C2 and C3 of the LDL-A module of Tva is an important determinant for ASLV-A entry. Thus, the present study provides strong evidence to support our hypothesis that one role of the N terminus of the LDL-A module of Tva is to allow proper folding and conformation of the protein for optimal interaction with the viral glycoprotein EnvA in ASLV-A entry.

scholarly journals GPNMB Extracellular Fragment Protects Melanocytes from Oxidative Stress by Inhibiting AKT Phosphorylation Independent of CD44

2021 ◽  
Vol 22 (19) ◽  
pp. 10843
Author(s):  
Qianqian Wang ◽  
Yasutaka Kuroda ◽  
Lingli Yang ◽  
Sylvia Lai ◽  
Yukiko Mizutani ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cancer Metastasis ◽  
Critical Role ◽  
Human Keratinocytes ◽  
Soluble Form ◽  
Epidermal Keratinocytes ◽  
Type I ◽  
Akt Phosphorylation ◽  
Transmembrane Glycoprotein

Glycoprotein non-metastatic melanoma protein B (GPNMB) is a type I transmembrane glycoprotein that plays an important role in cancer metastasis and osteoblast differentiation. In the skin epidermis, GPNMB is mainly expressed in melanocytes and plays a critical role in melanosome formation. In our previous study, GPNMB was also found to be expressed in skin epidermal keratinocytes. In addition, decreased GPNMB expression was observed in the epidermis of lesional skin of patients with vitiligo. However, the exact role of keratinocyte-derived GPNMB and its effect on vitiligo is still unknown. In this study, we demonstrated that GPNMB expression was also decreased in rhododendrol-induced leukoderma, as seen in vitiligo. The extracellular soluble form of GPNMB (sGPNMB) was found to protect melanocytes from cytotoxicity and the impairment of melanogenesis induced by oxidative stress. Furthermore, the effect of rGPNMB was not altered by the knockdown of CD44, which is a well-known receptor of GPNMB, but accompanied by the suppressed phosphorylation of AKT but not ERK, p38, or JNK. In addition, we found that oxidative stress decreased both transcriptional GPNMB expression and sGPNMB protein expression in human keratinocytes. Our results suggest that GPNMB might provide novel insights into the mechanisms related to the pathogenesis of vitiligo and leukoderma.

scholarly journals Contribution of the Periplasmic Chaperone Skp to Efficient Presentation of the Autotransporter IcsA on the Surface of Shigella flexneri

2008 ◽  
Vol 191 (3) ◽  
pp. 815-821 ◽  
Author(s):  
Jennifer K. Wagner ◽  
Jason E. Heindl ◽  
Andrew N. Gray ◽  
Sumita Jain ◽  
Marcia B. Goldberg
Keyword(s):  
Outer Membrane ◽  
Shigella Flexneri ◽  
Critical Role ◽  
Amino Terminus ◽  
Primary Role ◽  
Membrane Anchor ◽  
Bacterial Surface ◽  
Periplasmic Chaperone ◽  
Cell Spread

ABSTRACT IcsA is an outer membrane protein in the autotransporter family that is required for Shigella flexneri pathogenesis. Following its secretion through the Sec translocon, IcsA is incorporated into the outer membrane in a process that depends on YaeT, a component of an outer membrane β-barrel insertion machinery. We investigated the role of the periplasmic chaperone Skp in IcsA maturation. Skp is required for the presentation of the mature amino terminus (alpha-domain) of IcsA on the bacterial surface and contributes to cell-to-cell spread of S. flexneri in cell culture. A mutation in skp does not prevent the insertion of the β-barrel into the outer membrane, suggesting that the primary role of Skp is the folding of the IcsA alpha-domain. In addition, the requirement for skp can be partially bypassed by disrupting icsP, an ortholog of Escherichia coli ompT, which encodes the protease that processes IcsA between the mature amino terminus and the β-barrel outer membrane anchor. These findings are consistent with a model in which Skp plays a critical role in the chaperoning of the alpha-domain of IcsA during transit through the periplasm.

scholarly journals The Critical Role of Bach2 in Shaping the Balance between CD4+ T Cell Subsets in Immune-Mediated Diseases

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Lingyi Yang ◽  
Shuli Chen ◽  
Qiuyu Zhao ◽  
Ying Sun ◽  
Hong Nie
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Cell Biology ◽  
Transcriptional Activity ◽  
Critical Role ◽  
T Cell Subsets ◽  
B Cell Differentiation ◽  
Immune Mediated ◽  
B And T Lymphocytes

The transcription factor Bach2 which is predominantly expressed in B and T lymphocytes represses the expression of genes by forming heterodimers with small Maf and Batf proteins and binding to the corresponding sequence on the DNA. In this way, Bach2 serves as a highly conserved repressor which controls the terminal differentiation and maturation of both B and T lymphocytes. It is required for class switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes in activated B cells, and its function in B cell differentiation has been well-described. Furthermore, emerging data show that Bach2 regulates transcriptional activity in T cells at super enhancers or regions of high transcriptional activity, thus stabilizing immunoregulatory capacity and maintaining T cell homeostasis. Bach2 is also critical for the formation and function of CD4+ T cell lineages (Th1, Th2, Th9, Th17, T follicular helper (Tfh), and regulatory T (Treg) cells). Genetic variations within Bach2 locus are associated with numerous immune-mediated diseases including multiple sclerosis (MS), rheumatoid arthritis (RA), chronic pancreatitis (CP), type 2 chronic airway inflammation, inflammatory bowel disease (IBD), and type 1 diabetes. Here, we reveal a critical role of Bach2 in regulating T cell biology and the correlation with these immune-mediated diseases.

scholarly journals Critical role of novel Thr-219 autophosphorylation for the cellular function of PKCθ in T lymphocytes

2005 ◽  
Vol 24 (22) ◽  
pp. 3869-3880 ◽  
Author(s):  
Nikolaus Thuille ◽  
Isabelle Heit ◽  
Friedrich Fresser ◽  
Nina Krumböck ◽  
Birgit Bauer ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Critical Role ◽  
Cellular Function

scholarly journals A Pivotal Role for Interleukin-27 in CD8+T Cell Functions and Generation of Cytotoxic T Lymphocytes

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Noriko Morishima ◽  
Izuru Mizoguchi ◽  
Masae Okumura ◽  
Yukino Chiba ◽  
Mingli Xu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Critical Issue ◽  
Cell Functions ◽  
Antitumor Immunotherapy

Cytotoxic T lymphocytes (CTLs) play a critical role in the control of various cancers and infections, and therefore the molecular mechanisms of CTL generation are a critical issue in designing antitumor immunotherapy and vaccines which augment the development of functional and long-lasting memory CTLs. Interleukin (IL)-27, a member of the IL-6/IL-12 heterodimeric cytokine family, acts on naiveCD4+T cells and plays pivotal roles as a proinflammatory cytokine to promote the early initiation of type-1 helper differentiation and also as an antiinflammatory cytokine to limit the T cell hyperactivity and production of pro-inflammatory cytokines. Recent studies revealed that IL-27 plays an important role inCD8+T cells as well. Therefore, this article reviews current understanding of the role of IL-27 inCD8+T cell functions and generation of CTLs.

scholarly journals CRITICAL ROLE OF DETERMINANT PRESENTATION IN THE INDUCTION OF SPECIFIC RESPONSES IN IMMUNO-COMPETENT LYMPHOCYTES

1973 ◽  
Vol 137 (4) ◽  
pp. 967-990 ◽  
Author(s):  
David H. Katz ◽  
Emil R. Unanue
Keyword(s):  
T Cells ◽  
B Cells ◽  
T Lymphocytes ◽  
Cell Surface ◽  
Critical Role ◽  
Antibody Responses ◽  
Soluble Antigen ◽  
Protein Conjugates

A detailed analysis of the role of determinant presentation in the process of triggering immunocompetent lymphocytes has been made utilizing cell-bound hapten-carrier conjugates to elicit secondary antihapten antibody responses, primarily in vitro. The results of these experiments demonstrate that: (a) hapten-protein conjugates will attach to the surface membranes of macrophages directly, in the absence of specific antibodies, in a highly immunogenic form; (b) such macrophage-bound conjugates serve as remarkedly efficient stimuli to trigger both thymus-derived (T) and bone marrow-derived (B) cells in a specific manner, lowering the optimal threshold antigen dose (in molar terms) by several logs as compared with soluble antigen; (c) the macrophage is not unique in this regard, since fibroblasts are essentially comparable in the capacity to present antigen in highly immunogenic form; (d) cell surface-bound antigen clearly favors secondary in vitro responses of the IgG as compared with the IgM antibody class; (e) in terms of triggering B or T cells, antigen bound to macrophages in the form of immune complexes does not appear to possess any appreciable advantage over equimolar quantities of directly attached antigen; (f) the increased immunogenicity of cell-bound antigen appears to reflect certain crucial, and undefined, features of cell surface membranes and not merely the stabilization of determinants on a relatively immobile surface; and (g) although the efficiency of lymphocyte triggering is markedly enhanced by cell-bound antigen, the presence of macrophages is apparently not an absolute requirement for eliciting secondary in vitro antibody responses to soluble hapten-protein conjugates. The relevance of these observations to the nature of the signal induced upon antigen interaction by specific lymphocytes and the sequential cellular events involved in the regulatory influence of activated T cells on B cell responses to antigen is discussed. We postulate that T lymphocytes are best triggered by cell-bound antigen and that after this step the activated T lymphocytes regulate the triggering of B cells with antigen.

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