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T C Ryan

Publications and source records attributed to T C Ryan.

7 recordsLinked to original sources
PubMed2000

Desensitization of CXC chemokine receptor 4, mediated by IL-16/CD4, is independent of p56lck enzymatic activity.

CCR5 and CXC chemokine receptor 4 (CXCR4) are coreceptors for CD4 as defined by HIV-1 glycoprotein (gp) 120 binding. Pretreatment of T cells with gp120 results in modulation of both CCR5 and CXCR4 responsiveness, which is dependent upon p56(lck) enzymatic activity. The recent findings that pretreatment of T cells with a natural CD4 ligand, IL-16, could alter cellular responsiveness to macrophage-inflammatory protein-1ss (MIP-1ss) stimulation, prompted us to investigate whether IL-16 could also alter CXCR4 signaling. These studies demonstrate that IL-16/CD4 signaling in T lymphocytes also results in loss of stromal derived factor-1alpha (SDF-1alpha)/CXCR4-induced chemotaxis; however, unlike MIP-1ss/CCR5, the effects were not reciprocal. There was no effect on eotaxin/CCR3-induced chemotaxis. Desensitization of CXCR4 by IL-16 required at least 10-15 min pretreatment; no modulation of CXCR4 expression was observed, nor was SDF-1alpha binding altered. Using murine T cell hybridomas transfected to express native or mutated forms of CD4, it was determined that IL-16/CD4 induces a p56(lck)-dependent inhibitory signal for CXCR4, which is independent of its tyrosine catalytic activity. By contrast, IL-16/CD4 desensitization of MIP-1ss/CCR5 responses requires p56(lck) enzymatic activity. IL-16/CD4 inhibition of SDF-1alpha/CXCR4 signals requires the presence of the Src homology 3 domain of p56(lck) and most likely involves activation of phosphatidylinositol-3 kinase. These studies indicate the mechanism of CXCR4 receptor desensitization induced by a natural ligand for CD4, IL-16, is distinct from the inhibitory effects induced by either gp120 or IL-16 on CCR5.

Animals↗
PubMed2000

Interleukin 16: implications for CD4 functions and HIV-1 progression.

In this article, David Center and colleagues clarify the controversies that have emerged over the unique structure of interleukin 16 and its anti-HIV-1 activity. Interleukin 16 is a ligand for CD4, and this implies CD4 acts as a sentinel receptor that can switch CD4+ T cells between immune and inflammatory functions.

Animals↗
PubMed1999

Reciprocal desensitization of CCR5 and CD4 is mediated by IL-16 and macrophage-inflammatory protein-1 beta, respectively.

The ability of HIV-1 gp120 to inhibit chemokine signaling prompted us to determine whether signaling through CD4 by a natural ligand, IL-16, could alter cellular responsiveness to chemokine stimulation. These studies demonstrate that IL-16/CD4 signaling in T lymphocytes results in a selective loss of macrophage-inflammatory protein (MIP)-1 beta/CCR5-induced chemotaxis. There was no effect on monocyte chemoattractant protein-2/CCR1, -2, or -3-induced chemotaxis. Desensitization of CCR5 by IL-16 required at least 10 min of pretreatment; no modulation of CCR5 expression was observed, nor was MIP-1 beta binding to CCR5 altered. Using murine T cell hybridomas transfected to express native or mutated forms of CD4, it was determined that IL-16/CD4 induces a p56lck-dependent signal that results in desensitization of CCR5. The desensitization process is reciprocal and again selective, as prior CCR5 stimulation, but not CCR1, -2, or -3 stimulation, completely inhibits IL-16/CD4-induced T cell migration. Of interest, while p56lck enzymatic activity is not required for IL-16-induced migration, it was required for desensitization of CCR5. These studies indicate the existence of reciprocal receptor cross-desensitization between CD4 and CCR5 induced by two proinflammatory cytokines and suggest a selective relationship between the two receptors.

CCR5 Receptor Antagonists↗
PubMed1996

IL-16- and other CD4 ligand-induced migration is dependent upon protein kinase C.

Human interleukin-16, previously known as lymphocyte chemoattractant factor, is a CD4+ T cell competence growth factor initially described as a chemotactic factor for CD4+ cells. The interaction between IL-16 and its receptor CD4 leads to an increase in intracytoplasmic calcium and inositol triphosphate. Because of the association of intracellular shifts in protein kinase C (PKC) enzyme activity with production of these secondary messengers and the participation of PKC in transducing certain receptor-mediated migratory signals, we investigated the role of PKC in the CD4-mediated migratory response by IL-16. Recombinant IL-16 induces rapid translocation of PKC from the cytosol to the membrane in three separate CD4+ cell types: normal blood T cells, SUPT1 cells, and THP1 cells. PKC inhibitors H7, calphostin C, chelerythrine, and bisindolylmaleimide completely block IL-16-induced lymphocyte migration as well as the motile response induced by HIV-1 gp120 and anti-CD4 antibodies. Taken together, these data suggest a role for PKC in CD4-mediated migratory responses.

Antibodies, Monoclonal↗
PubMed1995

The CD4-associated tyrosine kinase p56lck is required for lymphocyte chemoattractant factor-induced T lymphocyte migration.

Lymphocyte chemoattractant factor (LCF) is a polypeptide cytokine which induces both cell motility and activation of T lymphocytes. These LCF-induced events demonstrate an absolute requirement for the cell surface expression of CD4. Because many CD4-mediated T lymphocyte activation events have been demonstrated to require the association of the src-related tyrosine kinase p56lck with the cytoplasmic domain of CD4, we examined the role of p56lck in LCF-induced lymphocyte migration in a murine T cell hybridoma line expressing transfected human CD4. LCF induces the catalytic activity of CD4 associated p56lck at chemoattractant concentrations of cytokine. Hybridoma cells that express CD4 with cytoplasmic point mutations which uncouple the CD4-lck association lack both lck enzymatic activity and chemotactic responses to LCF. The enzymatic activity of lck however does not appear to be required for CD4-mediated migratory signal. First, the protein tyrosine kinase inhibitor herbimycin A blocked LCF-induced p56lck activation but had no effect on the LCF-induced motile response. Second, T cell hybridomas expressing a chimeric receptor combining the extracellular domain of human CD4 and murine p56lck which lacked the kinase domain had a normal LCF-induced motile response. We conclude from these observations that CD4-lck coupling is essential for LCF-induced T lymphocyte migration but the motile response is independent of the enzymatic activity of CD4-associated p56lck.

Animals↗
PubMed1990

Measurement of superoxide release in the phagovacuoles of immune complex-stimulated human neutrophils.

Immune complex stimulation of human neutrophils elicits, among other events, the formation of phagocytic vacuoles into which the products of the stimulus activated oxidative burst and degranulation are released. In order to monitor burst activity in the phagocytic vacuole, we have developed a fluorochrome-coupled derivative of this neutrophil agonist. The fluorochrome 2',7'-dichlorodihydrofluorescein (DCFH) (the nonfluorescent, reduced form of 2',7'-dichlorofluorescein (DCF] has been covalently linked to bovine serum albumin (BSA), which can be used to form an immune complex with anti-BSA immunoglobulin. The resultant complex is an effective agonist for stimulating all immune complex-mediated neutrophil responses, as compared to nonderivatized controls. Upon exposure to hydrogen peroxide the stimulus-linked probe is converted to its oxidized, fully fluorescent form, the fluorescence of which is linearly related to the extent of probe oxidation. Using flow cytometry, we have demonstrated that the probe-stimulus complex is capable of monitoring the kinetics of the production of activated oxygen species by the membrane bound NADPH-oxidase enzyme, presumably within the phagocytic vacuoles of immune complex-activated neutrophils. We have found that the immune complex-mediated activation of the oxidative burst within the phagocytic compartment is preceded by a lag of approximately 30 s followed by a large sustained release of superoxide dependent hydrogen peroxide. Neutrophils from patients with chronic granulomatous disease, however, demonstrated no sustained increase in probe fluorescence, a finding consistent with the lack of oxidative burst activity in these cells. The DCFH-immune complex conjugate therefore provides an effective probe for monitoring the kinetics of the localized release of oxidative products within the forming phagocytic vacuoles of activated neutrophils, and may be used to further examine both the activation and activity of human neutrophils in response to 'physiologic' host defense agonists such as immune complexes.

Antigen-Antibody Complex↗