Dissection of T cell antigen receptor signaling using protein tyrosine kinase inhibitors

Baldari, Cosima T.; Telford, John L.

doi:10.1002/eji.1830240506

Cited by 9 publications

(3 citation statements)

References 54 publications

(35 reference statements)

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“…1B). In addition, CD4 signaling was inhibited by PTK inhibitors of the tyrphostin family, which block TcRmediated T cell activation [36], indicating that PTK activity is essential for CD4 signaling (Fig. 1 B).…”

Section: Characterization Of Cd4 Signaling To Nf-atmentioning

confidence: 90%

Distinct signaling properties identify functionally different CD4 epitopes

et al. 1995

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The CD4 coreceptor interacts with non-polymorphic regions of major histocompatibility complex class II molecules on antigen-presenting cells and contributes to T cell activation. We have investigated the effect of CD4 triggering on T cell activating signals in a lymphoma model using monoclonal antibodies (mAb) which recognize different CD4 epitopes. We demonstrate that CD4 triggering delivers signals capable of activating the NF-AT transcription factor which is required for interleukin-2 gene expression. Whereas different anti-CD4 mAb or HIV-1 gp120 could all trigger activation of the protein tyrosine kinases p56lck and p59fyn and phosphorylation of the Shc adaptor protein, which mediates signals to Ras, they differed significantly in their ability to activate NF-AT. Lack of full activation of NF-AT could be correlated to a dramatically reduced capacity to induce calcium flux and could be complemented with a calcium ionophore. The results identify functionally distinct epitopes on the CD4 coreceptor involved in activation of the Ras/protein kinase C and calcium pathways.

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Section: Characterization Of Cd4 Signaling To Nf-atmentioning

confidence: 90%

Distinct signaling properties identify functionally different CD4 epitopes

et al. 1995

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“…Finally, the biochemical events leading to a state of unresponsiveness as well as maintaining it are not well characterized; both the calcium influx and PKC activation play a major role (Dubois et al 1994). Stimulation of T cells by PMA and calcium ionophore can at least in part mimic TCR engagement (Baldari & Telford 1994). In this study we attempted to overcome antigen specific unresponsiveness or anergy from several angles.…”

mentioning

confidence: 99%

Specific T cell unresponsiveness in human filariasis: diversity in underlying mechanisms

Sartono

Kruize

Partònò

et al. 1995

Parasite Immunology

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In an attempt to overcome T cell unresponsiveness to filarial antigens, 65 individuals belonging to the three clinical groups of elephantiasis patients, microfilaraemics, and asymptomatic amicrofilaraemics who exhibited unresponsiveness to Brugia malayi adult worm antigen (BmA) were studied. Peripheral blood mononuclear cells were cocultured with antigen and one of the following reagents that have been reported to be effective in reconstituting T cell proliferation: interleukin-2 (IL-2), interleukin-7 (IL-7), anti-interleukin-4, anti-interleukin-10, anti-CD2, anti-CD27, anti-CD28, indomethacin, phorbol myristate acetate (PMA), or calcium ionophore (A23187). We were able to overcome antigen-specific unresponsiveness in only a minority of the individuals studied. Co-culture with IL-2, IL-7, indomethacin and PMA were the only conditions which resulted in enhanced proliferation to BmA in these individuals. In general, unresponsiveness in elephantiasis patients was easier to reverse than in other clinical groups: in 50% of elephantiasis patients, in 12.5% of microfilaraemics and in 20% of asymptomatic amicrofilaraemics. The results indicate that more than one distinct immunological mechanism may account for the antigen-specific unresponsiveness in individuals exposed to and infected with brugian filariasis.

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“…Inhibitors of T cell PTKs have been described in the literature which repress T cell activation and T cell-mediated cytotoxicity [83][84][85][86]. However, the fine specificity of these inhibitors are not known.…”

Section: Consequences Of Inhibiting Tcr Proximal Signalling Eventsmentioning

confidence: 99%

Role of tyrosine kinases in lymphocyte activation: Targets for drug intervention

1995

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Recent developments in our understanding of lymphocyte receptor-associated signalling events have offered many new potential targets for modifying antigen and cytokine receptor signalling events in immune-related diseases such as allergy, autoimmunity and transplant rejection. As discussed below, these targets are largely tissue-restricted and are functionally confined to a limited set of receptors. Therefore, it is anticipated that selective inhibitors of these signalling events would offer safe and effective therapies for immunologically-based diseases. First, we review T and B cell antigen receptor signalling as targets for inhibiting lymphocyte responses. Second, targets in lymphocyte cytokine receptor signalling pathways are discussed. Finally, we review strategies for inhibition of receptor signalling.

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Dissection of T cell antigen receptor signaling using protein tyrosine kinase inhibitors

Cited by 9 publications

References 54 publications

Distinct signaling properties identify functionally different CD4 epitopes

Distinct signaling properties identify functionally different CD4 epitopes

Specific T cell unresponsiveness in human filariasis: diversity in underlying mechanisms

Role of tyrosine kinases in lymphocyte activation: Targets for drug intervention

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