Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During embryonic development, T-lymphoid precursor cells colonize the thymus. Chemoattraction by the fetal thymus is thought to mediate T-precursor cell colonization. However, the molecules that attract T-precursor cells to the thymus remain unclear. By devising time-lapse visualization in culture, the present results show that alymphoid fetal thymus lobes attract T-precursor cells from fetal liver or fetal blood. CD4(-)CD8(-)CD25(-)CD44+ fetal thymocytes retained the activity to specifically re-enter the thymus. The attraction was predominantly due to I-A-expressing thymic epithelial cells and was mediated by pertussis toxin-sensitive G-protein signals. Among the chemokines produced by the fetal thymus, CCL21, CCL25, and CXCL12 could attract CD4(-)CD8(-)CD25(-)CD44+ fetal thymocytes. However, fetal thymus colonization was markedly diminished by neutralizing antibodies specific for CCL21 and CCL25, but not affected by anti-CXCL12 antibody. Fetal thymus colonization was partially defective in CCL21-deficient plt/plt mice and was further diminished by anti-CCL25 antibody. These results indicate that CCL21 is involved in the recruitment of T-cell precursors to the fetal thymus and suggest that the combination of CCL21 and CCL25 plays a major role in fetal thymus colonization.
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PMID:The role of CCL21 in recruitment of T-precursor cells to fetal thymi. 1535 18

Langerin/CD207 is a C-type lectin associated with formation of Birbeck granules (BG) in Langerhans cells (LC). Here, we describe a monoclonal antibody (mAb 205C1) recognizing the extracellular domain of mouse langerin. Cell-surface langerin was detected in all epidermal LC, which presented a uniform phenotype. Two subpopulations of langerin+ cells were identified in peripheral lymph nodes (LN). One population (subset 1) was CD11c(low/+)/CD8alpha(-/low)/CD11b+/CD40+/CD86+. The other population (subset 2) was CD11c(high)/CD8alpha+/CD11b(low), and lacked CD40 and CD86. Only subset 1 was fluorescein 5-isothiocyanate (FITC+) following painting onto epidermis, and the appearance of such FITC+ cells in draining LN was inhibited by pertussis toxin. Mesenteric LN, spleen, and thymus contained only a single population of langerin+ DC, corresponding to peripheral LN subset 2. Unexpectedly, BG were absent from spleen CD8alpha+ DC despite expression of langerin, and these organelles were not induced by mAb 205C1. Collectively, we demonstrate that two langerin+ DC populations (subsets 1 and 2) co-exist in mouse lymphoid tissue. Subset 1 unequivocally identifies epidermal LC-derived DC. The distribution of subset 2 indicates a non-LC origin of these langerin+ cells. These findings should facilitate our understanding of the role played by langerin in lymphoid organ DC subsets.
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PMID:Mouse lymphoid tissue contains distinct subsets of langerin/CD207 dendritic cells, only one of which represents epidermal-derived Langerhans cells. 1629

Factors governing the entry of cells into the postnatal thymus are poorly understood. We aimed to define molecular mechanisms mediating the homing of bone marrow cells to the thymus using a sublethally irradiated in vivo murine model. Entry of unfractionated and lineage-depleted bone marrow cells to the thymus, but not bone marrow, was a Galphai-mediated phenomenon. Lineage-depleted cells that had homed to the thymus expressed abundant CXCR4 and CCR5 mRNA, alone of 17 chemokine receptors evaluated by QPCR. Thymic-homed cells were distinct from cells that had homed to bone marrow in expression of CXCR4 and CCR5 by mRNA quantification and cell-surface expression of protein. Abrogation of CXCR4 and CCR5 function by genetic, antibody, or pharmacologic means impaired homing of lineage-depleted cells to the thymus, although not in a synergistic manner, implying interdependency of these receptors in the homing process. Competitive repopulation experiments demonstrated that inhibiting CXCR4-mediated homing adversely affected the double-negative cell pool at 2 weeks, suggesting that cells with prothymocytic activity may in part home via CXCR4. Overall, our data demonstrate differential homing mechanisms governing entry of unfractionated and lineage-depleted cells to irradiated bone marrow or thymus, with thymic homing of immature cells being pertussis-sensitive and mediated by the chemokine receptors CXCR4 and CCR5.
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PMID:CXCR4 and CCR5 mediate homing of primitive bone marrow-derived hematopoietic cells to the postnatal thymus. 1654 65

Macrophage-derived chemokine [CC chemokine ligand 22 (CCL22)] and thymus- and activation-regulated chemokine (CCL17) mediate cellular effects, principally by binding to their receptor CC chemokine receptor 4 (CCR4) and together, constitute a multifunctional chemokine/receptor system with homeostatic and inflammatory roles within the body. This study demonstrates that CCL22 and CCL17 stimulate pertussis toxin-sensitive elevation of intracellular calcium in the CEM leukemic T cell line and human peripheral blood-derived T helper type 2 (Th2) cells. Inhibition of phospholipase C (PLC) resulted in the abrogation of chemokine-mediated calcium mobilization. Chemokine-stimulated calcium responses were also abrogated completely by the inhibition of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] receptor-mediated calcium release. Chemotactic responses of CEM and human Th2 cells to CCL17 and CCL22 were similarly abrogated by inhibition of PLC and inhibition of novel, Ca2+-independent/diacylglycerol-dependent protein kinase C (PKC) isoforms. Inhibition of Ins(1,4,5)P3 receptor-mediated calcium release from intracellular stores had no effect on chemotactic responses to CCR4 ligands. Taken together, this study provides compelling evidence of an important role for PLC and diacylglycerol-dependent effector mechanisms (most likely involving novel PKC isoforms) in CCL17- and CCL22-stimulated, directional cell migration. In this regard, CCL22 stimulates phosphatidylinositol-3 kinase-independent phosphorylation of the novel delta isoform of PKC at threonine 505, situated within its activation loop--an event closely associated with increased catalytic activity.
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PMID:Evidence that phospholipase-C-dependent, calcium-independent mechanisms are required for directional migration of T-lymphocytes in response to the CCR4 ligands CCL17 and CCL22. 1661 59

Homing of bone marrow (BM)-derived progenitors to the thymus is essential for T cell development. We have previously reported that two subpopulations of common lymphoid progenitors, CLP-1 and CLP-2, coexist in the BM and give rise to lymphocytes. We demonstrate that CLP-2 migrate to the thymus more efficiently than any other BM-derived progenitors. Short-term adoptive transfer experiments revealed that CLP-2 homing involves P-selectin/P-selectin glycoprotein ligand 1 interactions, pertussis toxin-sensitive chemoattractant signaling by CC chemokine ligand 25 through CC chemokine receptor 9, and binding of the integrins alpha4beta1 and alphaLbeta2 to their respective ligands, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1. Preferential thymus-tropism of CLP-2 correlated with higher chemokine receptor 9 expression than on other BM progenitors. Thus, CLP access to the thymus is controlled by a tissue-specific and subset-selective multistep adhesion cascade.
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PMID:A multistep adhesion cascade for lymphoid progenitor cell homing to the thymus. 1664 Oct 96

Dendritic cell (DC) presentation of self antigen to thymocytes is essential to the establishment of central tolerance. We show here that circulating DCs were recruited to the thymic medulla through a three-step adhesion cascade involving P-selectin, interactions of the integrin VLA-4 with its ligand VCAM-1, and pertussis toxin-sensitive chemoattractant signaling. Ovalbumin-specific OT-II thymocytes were selectively deleted after intravenous injection of antigen-loaded exogenous DCs. We documented migration of endogenous DCs to the thymus in parabiotic mice and after painting mouse skin with fluorescein isothiocyanate. Antibody to VLA-4 blocked the accumulation of peripheral tissue-derived DCs in the thymus and also inhibited the deletion of OT-II thymocytes in mice expressing membrane-bound ovalbumin in cardiac myocytes. These findings identify a migratory route by which peripheral DCs may contribute to central tolerance.
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PMID:Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. 1695 87

Lysophosphatidic acid (LPA) is a bioactive lysophospholipid that signals through G protein-coupled receptors (GPCRs) to produce a range of biological responses. A recently reported fourth receptor, LPA(4)/GPR23, was notable for its low homology to the previously identified receptors LPA(1-3) and for its ability to increase intracellular concentrations of cAMP and calcium. However, the signaling pathways leading to LPA(4)-mediated induction of cAMP and calcium levels have not been reported. Using epitope-tagged LPA(4), pharmacological intervention, and G protein mini-genes, we provide independent confirmatory evidence that supports LPA(4) as a fourth LPA receptor, including LPA concentration-dependent responses and specific membrane binding. Importantly, we further demonstrate new LPA-dependent activities of LPA(4) that include the following: receptor internalization; G(12/13)- and Rho-mediated neurite retraction and stress fiber formation; G(q) protein and pertussis toxin-sensitive calcium mobilization and activation of a nonselective cation conductance; and cAMP increases mediated by G(s). The receptor is broadly expressed in embryonic tissues, including brain, as determined by Northern blot and reverse transcription-PCR analysis. Adult tissues have increased expression in skin, heart, and to a lesser extent, thymus. These data confirm the identification and extend the functionality of LPA(4) as an LPA receptor, bringing the number of independently verified LPA receptors to five, with both overlapping and distinct signaling properties and tissue expression.
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PMID:LPA(4)/GPR23 is a lysophosphatidic acid (LPA) receptor utilizing G(s)-, G(q)/G(i)-mediated calcium signaling and G(12/13)-mediated Rho activation. 1716 50

Sphingosine 1-phosphate (S1P), a pleiotropic lysophospholipid, regulates signal transduction pathway via G-protein-coupled receptors termed S1P1-5 in several types of the cells including lymphocytes. Higher levels of S1P4 mRNA as well as S1P1 mRNA are expressed in lymphoid tissues such as the spleen, thymus, lymph nodes, and Payer's patches. In contrast to S1P1 that plays an essential role in lymphocyte egress, little is known about the role of S1P4 in immune system. In this study, we found that S1P at 10 to 100 nM significantly induced the cell migration and the significant levels of S1P1 and S1P4 mRNA were expressed in mouse CD4 T cells, D10.G4.1 mouse Th2 cells, and EL-4.IL-2 mouse thymoma cells. In D10.G4.1 and EL-4.IL-2 cells, S1P-induced migration was almost completely inhibited by pretreatment with pertussis toxin, Clostoridium difficile toxin B, and (S)-enantiomer of FTY720-phosphate, a potent agonist at S1P1 and S1P4. The members of the Rho family small GTPase, Cdc42 and Rac were activated by S1P stimulation in these cells. The transfection with dominant negative or constitutively active forms of Cdc42 and Rac revealed that the activation of both Cdc42 and Rac is essential for S1P-induced migration of these cells. The immunoprecipitation assays using CHO cells co-expressing both S1P4 and S1P1 receptors indicated that S1P4 and S1P1 are associated on the cell surface. These results suggest that the association of S1P4 and S1P1 plays an important role in migratory response of mouse T cells toward S1P.
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PMID:Involvement of sphingosine 1-phosphate (S1P) receptor type 1 and type 4 in migratory response of mouse T cells toward S1P. 1725 96

Experimental autoimmune encephalomyelitis (EAE) is commonly regarded as an animal model of the human disease multiple sclerosis (MS). Pertussis toxin (PTX) is routinely used for EAE induction in mice. Besides opening the blood-brain barrier, it acts as an adjuvant causing strong expansion of antigen-specific cells after coinjection with neuroantigens in IFA. Using an IL-17 ELISPOT assay we developed previously, we investigated the capability of PTX to induce proteolipid protein peptide 139-151(PLPp)-specific Th-17 cells in the immune periphery and in the thymus after coinjection with PLPp/IFA. PTX was found to induce peripheral PLPp-specific Th-17 cells in the draining lymph node and in the spleen, but not in the thymus. Our study indicates a new mechanism by which microbial agents can initiate or maintain autoimmune reactions and supports the growing role in particular for Th-17 cells in organ-specific autoimmune diseases like multiple sclerosis or EAE.
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PMID:The PLPp-specific T-cell population promoted by pertussis toxin is characterized by high frequencies of IL-17-producing cells. 1788 Dec 43

Demonstration of thymic homing dependent on Galphai proteins is one of the keys to determine whether thymic entrance of blood-borne progenitors is a highly selective process. The present study provides compelling evidence of an indispensable role for Galphai proteins in this process. Absence of either Galphai2 or Galphai3 significantly abrogated thymic homing, with an effect of Galphai3 being greater than that of Galphai2. Pertussis toxin treatment that blocks both Galphai2 and Galphai3 almost completely blocked thymic seeding in the thymus. Null mutation of Galphai3 also hindered bone marrow cell development and thus reduced production of pre-thymic progenitors. In contrast, Galphai2 exhibited a more prominent role than Galphai3 in guidance of CD4-CD8--double negative (DN) 1 cell migration and early thymic differentiation. The Galphai-deficiency-induced defects might be compensated for in part via augmented function of thymic stromal cells so that a nearly normal output of mature T cells could be maintained in these Galphai-deficient mice. These studies underscore the importance of Galphai in regulating thymic homing and pre-thymic and early thymocyte differentiation.
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PMID:Requirement of Galphai in thymic homing and early T cell development. 1850 27


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