Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.4 (trypsin)
 42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of class II MHC-restricted keyhole limpet hemocyanin-specific Th cell clones were examined for cytoplasmic granules by histochemical techniques and fractionation of their homogenates. All showed granules containing lysosomal enzymes and high levels of trypsin-like activity revealed by a N-alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester-esterase assay. Using the latter as a marker for granule contents, granule secretion was observed in response to MHC-restricted, Ag-dependent signals presented in vitro, and correlated well with T cell activation as measured by proliferation. However, human rIL-2, a strong inducer of T cell proliferation, did not stimulate N-alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester-esterase secretion by itself, nor did it influence the secretion mediated by Ag. Other factors found to induce secretion included immobilized antibodies directed against determinants of the TCR complex, as well as Con A. These results suggest that granule enzyme secretion is another indicator of TCR-mediated activation and provides a possible mechanism for Th cell function via a rapid, local delivery of granule contents to adjacent cells.
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PMID:T helper cell cytoplasmic granules. Exocytosis in response to activation via the T cell receptor. 296 63

Lymphohematopoiesis, cell matrix adhesion, homing of leukocytes, T cell activation, and tumor metastasis are mediated through the CD44 family of cell surface receptors. We have recently shown that anti-CD44 mAb trigger protein tyrosine kinase-dependent activation of T cell effector functions. Here, we show that hyaluronate (HA), a CD44 ligand, in conjunction with CD3/TCR-mediated stimuli, is costimulatory for human peripheral blood T cell proliferation, for IL-2 production by Th clones, and for release of trypsin-like esterase by cytolytic T cell clones. A human T cell line, HUT-78, was found to bind HA and on HA coating it was used as a target for cytolytic T cell clones. After anti-CD3 stimulation, CD3+/CD8+ clones acquire the ability of lysing HA-coated HUT-78 cells more efficiently than the same HA-uncoated targets. Resting peripheral blood T cells and T cell clones do not adhere to HA-coated plates. However, 24-h anti-CD3 mAb stimulation gives them the transient ability to bind HA. HA adhesion of activated T cells and T cell clones, as well as that of T cell lines, is blocked by one anti-CD44 mAb (J-173). Two other anti-CD44 mAbs induce a 10-fold increase in HA adhesiveness of anti-CD3-stimulated peripheral blood T cells. This impressive HA adhesiveness is also readily blocked by J-173 anti-CD44 mAb. These data indicate that 1) HA is costimulatory for human T cell effector functions in conjunction with CD3/TCR-mediated stimuli, 2) the capacity to bind HA is acquired by resting T cells and T cell clones after anti-CD3 stimulation, and 3) HA binding occurs via specific interaction with CD44 molecules expressed on activated T cells.
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PMID:Hyaluronate is costimulatory for human T cell effector functions and binds to CD44 on activated T cells. 751 23

The mAb A6 was produced by immunization of mice with human PHA-stimulated PBMC. Immunoprecipitation studies and staining of cell lines transfected with individual leukocyte common antigen (LCA) isoforms showed that A6 recognizes a unique epitope strongly expressed on the lower MW isoform (p180) of LCA, but also weakly expressed on the p190 isoform coded by exon B and the p205 coded by exons A and B. The epitope recognized by A6 was carbohydrate-dependent in that it was neuraminidase-sensitive, but trypsin-resistant. A6 strained most TCR-alpha beta+ cells with differential intensities, subdividing them into a bright and dim population, and strongly stained all TCR-gamma delta+ cells. A6 did not stain CD19+ B cells nor CD56+ NK cells. Anti-CD45 mAb such as UCHL1 recognizing CD45RO have been used to define memory T cells. Depletion of PBMC subsets with A6 or UCHL1 mAb dramatically decreased proliferative responses to the recall antigens anti-CD3 mAb and alloantigen and enhanced their responses to PHA. A6, unlike UCHL1, also depleted alloreactive T cells that affect primary and secondary MLC and CML. Thus, A6 was shown to recognize the lower MW isoforms of LCA which are expressed on functional T cell subsets including memory, activated, and alloreactive T cells.
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PMID:A monoclonal antibody (A6) recognizing a unique epitope restricted to CD45RO and RB isoforms of the leukocyte common antigen family identifies functional T cell subsets. 752 74

CD6 is a 130-kD glycoprotein expressed on the surface of thymocytes and peripheral blood T cells that is involved in TCR-mediated T cell activation. In thymus, CD6 mediates interactions between thymocytes and thymic epithelial (TE) cells. In indirect immunofluorescence assays, a recombinant CD6-immunoglobulin fusion protein (CD6-Rg) bound to cultured human TE cells and to thymic fibroblasts. CD6-Rg binding to TF and TE cells was trypsin sensitive, and 54 +/- 4% of binding was divalent cation dependent. By screening the blind panel of 479 monoclonal antibodies (mAbs) from the 5th International Workshop on Human Leukocyte Differentiation Antigens for expression on human TE cells and for the ability to block CD6-Rg binding to TE cells, we found one mAb (J4-81) that significantly inhibited the binding of CD6-Rg to TE cells (60 +/- 7% inhibition). A second mAb to the surface antigen identified by mAb J4-81, J3-119, enhanced the binding of CD6-Rg to TE cells by 48 +/- 5%. Using covalent cross-linking and trypsin digestion, we found that mAb J4-81 and CD6-Rg both bound to the same 100-kD glycoprotein (CD6L-100) on the surface of TE cells. These data demonstrate that a 100-kD glycoprotein on TE cells detected by mAb J4-81 is a ligand for CD6.
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PMID:Identification and characterization of a 100-kD ligand for CD6 on human thymic epithelial cells. 753 42

Cadherins mediate homotypic intercellular adhesion in epidermis and other epithelia. E-cadherin is also involved in interactions between murine epidermal Langerhans cells (LC) and keratinocytes (KC). Dendritic epidermal T cells (DETC) comprise another subpopulation of epidermal leukocytes. Using flow cytometry, we determined that DETC expressed levels of E-cadherin similar to those expressed by LC and KC. DETC also adhered congruent to three-fold better to KC and E-cadherin-transfected fibroblasts than to normal fibroblasts. Treatment of DETC with trypsin in the absence of calcium caused a loss of E-cadherin and resulted in an congruent to 80% decrease in DETC-KC adhesion whereas treatment of DETC with trypsin in the presence of calcium did not significantly affect E-cadherin expression or DETC-KC binding. Thus, E-cadherin may be involved in adhesion of DETC to KC. DETC are derived from TCR V gamma 3+ thymocytes that transiently populate embryonic murine thymus. We determined that TCR V gamma 3+ thymocytes as well as other early (fetal day 16) TCR gamma/delta+ thymocytes expressed E-cadherin; TCR gamma/delta+ (TCR V gamma 3-) thymocytes that developed later did not. These results indicate that cells of the T cell lineage can express E-cadherin, and suggest that E-cadherin may play a role in adhesion of DETC (and/or DETC precursors) to KC.
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PMID:Murine dendritic epidermal T cells (DETC) express the homophilic adhesion molecule E-cadherin. 755 Jun 6

We show that antibodies to the CD44 molecule trigger proliferation of human CD3+/CD4+ T-cell clones. Such effect is IL2-dependent, as shown by IL2 production induced by anti-CD44 mAb and by inhibition of cell proliferation in the presence of anti-IL2 antibodies or cyclosporin A (CsA). Moreover, anti-CD44 mAb triggered human cytolytic CD4+ and CD8+ TCR alpha/beta+ clones, and V delta 1 or V delta 2 TCR Y/delta+ clones to lyse Fc-gamma-R+ P815 cells and to release granule trypsin-like esterase enzymes. Anti-CD44 mAb-triggered proliferation and cytotoxicity were blocked by the PTK-inhibitor, genestein. In addition, ligation of the CD44 molecule induced tyrosine phosphorylation of proteins identical, by molecular weight, to those phosphorylated following anti-CD3 mAb-stimulation. Notably, anti-CD44 mAb does not induce tyrosine phosphorylation of a 21 kD protein (the phosphorylated zeta chain of the TcR molecular complex) typically observed upon anti-CD3 mAb stimulation.
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PMID:Ligation of the lymphocyte homing receptor CD44 triggers T-helper and cytolytic functions of human T cells. 776 33

mAb against the lymphocyte homing receptor CD44/Hermes up-regulate the proliferation of human T PBL induced by anti-CD3 or anti-CD2 mAb. Moreover, certain anti-CD44 mAb can activate human resting T cells and mouse cytotoxic T cells in the absence of anti-CD3 or anti-CD2 mAb. Here, we show that anti-CD44 mAb trigger proliferation of human CD3+/CD4+ T cell clones in a fashion similar to that observed with mAb to CD3. Such an effect is IL-2-dependent, as shown by IL-2 production induced by anti-CD44 mAb and by complete inhibition of cell proliferation in the presence of anti-IL-2 antibodies or cyclosporin A. Moreover, anti-CD44 mAb trigger human cytolytic T cell clones to lyse Fc gamma-R+ P815 cells in the absence of additional stimuli. The magnitude of the cytolytic response induced by anti-CD44 mAb is comparable to that observed in the presence of anti-CD3 mAb for both CD4+ and CD8+ TCR-alpha/beta+ clones, and for V delta 1 or V delta 2 TCR-gamma/delta+ clones. By contrast, in CD3-/CD16+ NK cell clones, no cytolytic responses to anti-CD44 mAb could be observed. Granule trypsin-like esterase enzyme (granzyme) release by cytolytic T cell clones is induced by plastic-immobilized anti-CD44 mAb. Anti-CD44 mAb-triggered proliferation ([3H]thymidine incorporation) and cytotoxicity are blocked by the protein tyrosine kinase inhibitor, genestein. In addition, ligation of the CD44 molecule induces tyrosine phosphorylation of proteins identical, by molecular mass, to those phosphorylated after anti-CD3 mAb stimulation. Notably, anti-CD44 mAb does not induce tyrosine phosphorylation of a 21-kDa protein (the phosphorylated zeta-chain of the TCR molecular complex) typically observed upon anti-CD3 mAb stimulation. In conclusion, this study shows that the ligated CD44 molecule provides the necessary stimuli for a variety of T cell-mediated functions triggered via protein tyrosine kinase-dependent signal transduction pathways at least in part similar to those that follow stimulation of the CD3/TCR complex.
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PMID:Antibodies to CD44 trigger effector functions of human T cell clones. 809 50

PBK101 was a thymic T cell line of AKR/J origin that expressed Thy 1, CD44, IL-2R, and VLA-4 antigens but not CD4, CD8, or the TCR/CD3 complex. PBK101 was initially isolated growing together with adherent thymic stromal cells. The proliferation of PBK101 ceased when it was cultured in the absence of stromal cells and its proliferation was stimulated when stromal cells were added back to the culture. PBK101 cells were also stimulated when cocultured with peritoneal exudate cells (PEC). These responses appeared to require contact between PBK101 and the cellular stimulators. The stimulatory activity of the thymic stromal cell line remained in culture wells after the cellular elements were removed by mild trypsinization or detergent extraction indicating that a stimulatory molecule(s) was associated with extracellular matrix (ECM). The activity of the ECM was resistant to high salt extraction, acetic acid, and strong denaturants but was sensitive to treatment with trypsin, heat (80 degrees C), and, if cells were treated with a lathyragen, 4 M guanidine-HCl plus 2 mM dithiothreitol (DTT). The extracellular matrix produced by some other fibroblast cell lines was nonstimulatory. Stimulation of PBK101 by ECM was not inhibited by monoclonal anti-VLA4 or polyclonal anti-fibronectin antisera. Purified extracellular matrix proteins (laminin, collagen, fibronectin, and vitronectin) were either nonstimulatory or only marginally stimulated PBK101 cells. These results suggested that a potentially novel molecule(s) present in the extracellular matrix of a thymic stromal cell line and on the surface of other cellular elements stimulated a thymic T cell line of immature phenotype. The potential role of extracellular matrix-associated molecules in normal T cell development is discussed.
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PMID:Extracellular matrix-induced stimulation of a CD4-8- thymic T cell line. 816 42

Human alpha-thrombin stimulated five different T lymphoblastoid cell lines to increase intracellular free Ca2+ concentrations, whereas five B cell lines did not similarly respond. The T cell intracellular free Ca2+ increased rapidly, plateaued within 10 to 20 s, and then declined without any measurable sustained intracellular free Ca2+ elevation. Liberation of inositol trisphosphate peaked within 60 s, and a rapid and sustained activation of protein kinase C was induced. The thrombin-specific inhibitor, hirudin, completely blocked the response to alpha-thrombin. Catalytically inactivated forms of alpha-thrombin failed to stimulate the T cells, whereas trypsin, gamma-thrombin (which lacks fibrinogen clotting activity), or the synthetic 14-amino acid thrombin receptor-activation peptide stimulated T cells, but required approximately 10-, approximately 15-, or approximately 100-fold higher concentrations, respectively, when compared to alpha-thrombin. Stimulation by thrombin receptor-activation peptide was desensitized by alpha-thrombin, and vice versa, but alpha-thrombin did not desensitize stimulation by mAb to the TCR/CD3 Ag. The presence of the receptor on T but not on B cells was confirmed by flow-cytometric analysis using a mAb against the human thrombin receptor. These findings demonstrate functional thrombin receptors on T lymphoblastoid cells that may be capable of activating the cells, independently of an ongoing immune response.
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PMID:Functional thrombin receptors on human T lymphoblastoid cells. 838 23

Recent studies in several laboratories have advanced the concept that during cellular rejection, the allograft undergoes a stress response which regulates the expression of stress proteins (or heat shock proteins, hsp) and triggers the recruitment and activation of hsp-reactive lymphocytes. In a rat model of heterotopic heart transplants we have found that allograft-infiltrating lymphocytes respond to recombinant mycobacterial hsp and irradiated syngeneic spleen cells as a source of self-APC (antigen-presenting cells). This report describes T cell clones generated by culturing ACI into Lewis rat cardiac allograft-derived lymphocytes with mycobacterial hsp71, syngeneic spleen cells and IL-2 (interleukin-2). Two groups of self-APC-reactive T cell clones have been distinguished, all of them are CD3+, CD4+, CD8-. One group is referred to as hsp71-dependent, autoreactive T cells because these clones respond to self-APC but only in the presence of hsp71. No reactivity is seen with mycobacterial hsp65 or when hsp71 is tested with allo-PC from ACI donors or third-party APC from Brown Norway (BN) rats. Treatment of hsp71 with trypsin, polymyxin B or ATP-agarose chromatography abrogates the hsp71 effect thus indicating that structurally intact hsp71 must interact with self-APC which then activate hsp71-dependent, autoreactive T cells. The second group of clones reacts to self-APC and while their response does not require the presence of hsp71, their proliferation is often augmented by hsp71 but not by hsp65. These hsp71-independent, autoreactive clones do not respond to allo-APC from ACI donors or third-party APC from BN rats. Polymyxin or trypsin treatment had no significant effect on their proliferative responses. The data with the anti-TCR-alpha beta monoclonal antibody R73 offer additional evidence for two functionally different types of self-APC reactive CD4 cells infiltrating the allograft. R73 inhibits the proliferation of self-APC induced responses of hsp-71-independent clones as well as the allo-APC induced responses of alloreactive T cell clones. In contrast, this antibody augments the responses of hsp71-dependent T cells. Moreover, these clones can also proliferate in response to self-APC when hsp71 is substituted by R73. The hsp71-dependency of self-APC reactive T cell reactivity represents a previously unrecognized mechanism of cellular immunity to allografts. This mechanism might be related to the peptide binding properties of hsp71 and the ability of stress proteins to function as molecular chaperones in antigen processing.
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PMID:Identification of two types of autoreactive T lymphocyte clones cultured from cardiac allograft-infiltrating cells incubated with recombinant mycobacterial heat shock protein 71. 910 36


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