Abnormal T cells from MRL/Mp-lpr/lpr mice do not respond to anti-T-cell-receptor antibody or tumor promoter and calcium lonophore A23187 despite the presence of the T-cell-receptor complex and protein kinase c

Integrin receptor signals are costimulatory for mitogenesis with the T-cell receptor during T-cell activation. A subset of integrin receptors can link to the adapter protein Shc and provide a mitogenic stimulus. Using a combination of genetic and pharmacological approaches, we show herein that integrin signaling to Shc in T cells requires the receptor tyrosine phosphatase CD45, the Src family kinase member Lck, and protein kinase C. Our results suggest a model in which integrin-dependent serine phosphorylation of Lck is the critical step that determines the efficiency of Shc tyrosine phosphorylation in T cells. Serine phosphorylation of Lck is dependent on PKC and is also linked to CD45 dephosphorylation. Mutants of Lck that cannot be phosphorylated on the critical serine residues do not signal efficiently to Shc and have greatly reduced kinase activity. This signaling from integrins to Lck may be an important step in the costimulation with the T-cell receptor during lymphocyte activation.

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Protein kinase C is required for responses to T cell receptor ligands but not to interleukin-2 in T cells

Cell ◽

10.1016/0092-8674(88)90013-x ◽

1988 ◽

Vol 55 (1) ◽

pp. 101-112 ◽

Cited By ~ 126

Author(s):

Viia E. Valge ◽

Justin G.P. Wong ◽

Barry M. Datlof ◽

Anthony J. Sinskey ◽

Anjana Rao

Keyword(s):

T Cells ◽

Protein Kinase C ◽

T Cell ◽

Protein Kinase ◽

T Cell Receptor ◽

Interleukin 2 ◽

Cell Receptor ◽

Receptor Ligands ◽

Kinase C

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Cyclosporine A inhibits Ca2+-dependent stimulation of the Na+/H+ antiport in human T cells.

The Journal of Cell Biology ◽

10.1083/jcb.103.2.457 ◽

1986 ◽

Vol 103 (2) ◽

pp. 457-463 ◽

Cited By ~ 38

Author(s):

P M Rosoff ◽

G Terres

Keyword(s):

T Cells ◽

Protein Kinase C ◽

T Cell ◽

Protein Kinase ◽

T Cell Receptor ◽

Rat Kidney ◽

Cell Receptor ◽

Kinase C ◽

Normal Rat ◽

Stimulation Of

The cyclic undecapeptide cyclosporine A (CsA) is a potent immunosuppressive agent that inhibits the initial activation of T lymphocytes. This agent appears to be most effective in blocking the action of mitogens such as concanavalin A and the calcium ionophore A23187, which cause an influx of Ca2+, but not those that may act by alternate mechanisms. These observations suggest that CsA may block a Ca2+-dependent step in T cell activation. We have shown that stimulation of the T3-T cell receptor complex-associated Ca2+ transporter activates the Na+/H+ antiport (Rosoff, P. M., and L. C. Cantley, 1985, J. Biol. Chem., 260: 14053-14059). The tumor-promoting phorbol esters, which are co-mitogenic for T cells, activate the exchanger by a separate pathway which is mediated by protein kinase C. Both the rise in intracellular Ca2+ and intracellular pH may be necessary for the successful triggering of cellular activation. In this report we show that CsA blocks the T3-T cell receptor-stimulated, Ca2+ influx-dependent activation of Na+/H+ exchange, but not the phorbol ester-mediated pathway in a transformed human T cell line. CsA inhibited mitogen-stimulation of interleukin-2 production in a separate cell line. CsA also inhibited vasopressin stimulation of the antiporter in normal rat kidney fibroblasts, but had no effect on serum or 12-O-tetradecanoyl phorbol 13-acetate stimulation. CsA did not affect serum or vasopressin or serum stimulation of normal rat kidney cell proliferation. CsA also had no effect on lipopolysaccharide or phorbol ester stimulation of Na+/H+ exchange activity or induction of differentiation in 70Z/3 pre-B lymphocytes in which these events are initiated by the protein kinase C pathway. These data suggest that mechanisms of activation of Na+/H+ exchange that involve an elevation in cytosolic Ca2+ are blocked by CsA but that C kinase-mediated regulation is unaffected. The importance of the Na+/H+ antiport in the regulation of growth and differentiation of T cells is discussed.

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Stimulation of T cells through the CD3/T-cell receptor complex: role of cytoplasmic calcium, protein kinase C translocation, and phosphorylation of pp60c-src in the activation pathway.

Molecular and Cellular Biology ◽

10.1128/mcb.7.2.650 ◽

1987 ◽

Vol 7 (2) ◽

pp. 650-656 ◽

Cited By ~ 44

Author(s):

J A Ledbetter ◽

L E Gentry ◽

C H June ◽

P S Rabinovitch ◽

A F Purchio

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Solid Phase ◽

Interleukin 2 ◽

Cell Receptor ◽

Jurkat Cells ◽

Receptor Complex ◽

Kinase C ◽

Stimulation Of

Stimulation of T cells or the Jurkat T-cell line with soluble antibodies to the CD3/T-cell receptor complex causes mobilization of cytoplasmic Ca2+, which is blocked by pertussis toxin but not by ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, and translocation of protein kinase C activity from the cytoplasm to the membrane. Such stimulation also causes phosphorylation of pp60c-src at an amino-terminal serine residue. These activities are consistent with induction of phosphatidylinositol metabolism after antibody binding. Anti-CD3 stimulation with antibody in solution, however, does not cause Jurkat cells to release interleukin 2 and blocks rather than induces proliferation of T cells. Induction of interleukin 2 production by Jurkat cells and proliferation by normal T cells requires anti-CD3 stimulation with antibody on a solid support, such as Sepharose beads or a plastic dish. Thus, we examined phosphorylation of pp60c-src after stimulation of Jurkat cells with anti-CD3 in solution or on solid phase. Both of these caused serine phosphorylation of pp60c-src that was indistinguishable even after 4 h of stimulation. These results indicate that the mode of anti-CD3 stimulation (in solution or on solid phase) controls a cellular function that modifies the consequences of signal transduction through phosphatidylinositol turnover.

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