Cytotoxic T lymphocyte‐associated antigen‐4 inhibits integrin‐mediated stimulation

Gatta, Lucia; Calviello, Gabriella; Nicuolo, Fiorella Di; Pace, Luigia; Ubaldi, Vanessa; Doria, Gino; Pioli, Claudio

doi:10.1046/j.1365-2567.2002.01493.x

Cited by 15 publications

(10 citation statements)

References 43 publications

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“…These findings support a reverse stop-signaling mechanism for modulating the threshold of T cell activation by CTLA-4 [45]. It has been reported that CTLA-4 inhibits the activation of transcription factors such as NF-κB, NF-AT and AP-1 [46] as well as Ca 2+ mobilization and PLC-γ1 phosphorylation in activated T cells in vitro [47]. CTLA-4 can also target activation of the type II serine/threonine phosphatase PP2A in human CD4 + T cells [48].…”

Section: Ctla-4 Is An Immune Checkpoint Moleculesupporting

confidence: 65%

Blockade of cytotoxic T-lymphocyte antigen-4 as a new therapeutic approach for advanced melanoma

Wang

Zuo

Sarkar

et al. 2011

Expert Opinion on Pharmacotherapy

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Introduction The incidence of melanoma continues to rise and prognosis in patients with metastatic melanoma remains poor. The cytotoxic T-lymphocyte antigen-4 (CTLA-4) serves as one of the primary immune checkpoints and downregulates T cell activation pathways. Enhancing T cell activation by antibody blockade of the CTLA-4 provides a novel approach to overcome tumor-induced immune tolerance. Recently, anti-CTLA-4 therapy demonstrated significant clinical benefit in patients with metastatic melanoma, which led to the approval of ipilimumab by the Food and Drug Administration in early 2011. Areas covered The fundamental concepts underlying CTLA-4 blockade-potentiated immune activation, the scientific rationale for and the preclinical evidence supporting CTLA-4-targeted cancer immunotherapy are presented. We also provide an update on clinical trials with anti-CTLA-4 inhibitors and discuss the associated autoimmune toxicity. Expert opinion Given that overall survival is the only validated endpoint for the anti-CTLA-4 therapy, the clinical implications of the antigen or tumor-specific immunity in patients remain to be clarified. Additional research is necessary to elucidate the prognostic significance of immune-related side effects and significantly optimize the treatment regimens. An improved understanding of the mechanisms of action of CTLA-4 antibodies may also culminate in wide-ranging clinical applications of this novel therapy for other tumor types.

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Section: Ctla-4 Is An Immune Checkpoint Moleculesupporting

confidence: 65%

Blockade of cytotoxic T-lymphocyte antigen-4 as a new therapeutic approach for advanced melanoma

Wang

Zuo

Sarkar

et al. 2011

Expert Opinion on Pharmacotherapy

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“…Additionally, while increased ERK activity may activate Elk-1 and induce Fos transcription required to drive the IL-2 promoter, inhibition of IL-2 transcription by CTLA-4 may not be fully reversed by blocking Rap1 activation, as signaling to other relevant transcription factors may remain inhibited by CTLA-4 (18). We asked whether additional inhibitory mechanisms were still functioning in Rap1GAP1-expressing T cells by examining TCR-dependent tyrosine phosphorylation of PLC␥1 (19). CTLA-4 inhibited the phosphorylation of PLC␥1 in Rap1GAP1-expressing as well as wild-type T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Some of these pathways include inhibition of PLC␥, the recruitment of the SHP-2 phosphatase (10), and regulation of ERK-independent transcription factors that remain inhibited by CTLA-4 (18). To confirm that ERK-independent actions of CTLA-4 were retained in the Rap1GAP1-transgenic T cells, we examined TCR-dependent tyrosine phosphorylation of PLC␥1 (19). CTLA-4 inhibited the phosphorylation of PLC␥1 in Rap1GAP1-expressing as well as wild-type T cells (Fig.…”

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confidence: 99%

Regulation of the Small GTPase Rap1 and Extracellular Signal-Regulated Kinases by the Costimulatory Molecule CTLA-4

Dillon

Carey

Wetzel

et al. 2005

Molecular and Cellular Biology

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The mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) is activated following engagement of the T-cell receptor and is required for interleukin 2 (IL-2) production and T-cell proliferation. This activation is enhanced by stimulation of the coreceptor CD28 and inhibited by the coreceptor CTLA-4. We show that the small G protein Rap1 is regulated in the opposite manner; it is inhibited by CD28 and activated by CTLA-4. Together, CD3 and CTLA-4 activate Rap1 in a sustained manner. To delineate T-cell function in the absence of Rap1 activity, we generated transgenic mice expressing Rap1GAP1, a Rap1-specific GTPaseactivating protein. Transgenic mice showed lymphadenopathy, and transgenic T cells displayed increased ERK activation, proliferation, and IL-2 production. More significantly, the inhibitory effect of CTLA-4 on T-cell function in Rap1GAP1-transgenic T cells was reduced. We demonstrate that CTLA-4 activates Rap1, and we propose that intracellular signals from CTLA-4 antagonize CD28, at least in part, at the level of Rap1.The activation of T cells requires antigen recognition through the T-cell receptor (TCR) and costimulation via the CD28 coreceptor, which binds the family of B7 ligands (B7-1 and B7-2) expressed on antigen-presenting cells (APCs) (35). Additional complexity comes with another coreceptor, CTLA-4, that also binds B7 and can antagonize the ability of CD28 to stimulate T-cell activation and interleukin 2 (IL-2) accumulation (25,27,28,42,44). Recent studies have suggested that inhibition of extracellular signal-regulated kinases (ERKs) may contribute to this action (6, 9, 38). ERKs are activated following costimulation by TCR/CD28 and are required for AP-1-dependent transcription of IL-2, a cytokine that is essential for T-cell proliferation (32, 46). Cross-linking anti-CTLA-4 antibodies (that activate CTLA-4) inhibit both ERK activation and IL-2 production following costimulation by TCR/CD28 (6, 9). The mechanism by which CTLA-4 inhibits ERK activation is not known.The small G protein Ras mediates TCR activation of ERKs (7). TCR stimulation triggers the activation of Ras via the Ras guanine nucleotide exchange factors (GEF) Cal DAG-GEF II (also called Ras-GRP1) (17) and SOS (47). Ras is a positive activator of the mitogen-activated protein (MAP) kinase kinase kinase Raf-1 that can phosphorylate and activate the MAP kinase kinase MEK, which, in turn, can activate ERK. Potential negative regulatory molecules are also activated by TCR stimulation. One of these is the small G protein Rap1 that, like Ras, can be inhibited by specific GTPase-activating proteins (Rap1GAPs). Rap1 is activated following stimulation of the TCR (1, 8) and, like Ras, is rapidly recruited to the plasma membrane upon activation (3). During CD28 costimulation, Rap1 activation is inhibited (8,22,33) and ERK signaling is enhanced (8). Conversely, T lymphocytes lacking the Rap1GAP Spa-1 show constitutively elevated Rap1 activity, diminished ERK activation, and a decreased response to TCR stimulation (21). ...

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“…The intensity of the bands was directly quantified by ImageQuant software (Molecular Dynamics), which gives rise to a volume report by integrating the area of the band and its intensity. Results are shown after normalization with ␤-actin (26). Abs were subsequently stripped off from membranes for reprobing as described above.…”

Section: Western Blot (Wb)mentioning

confidence: 99%

IL-4 Modulation of CD4+CD25+ T Regulatory Cell-Mediated Suppression

Pace

Pioli

Doria

2005

The Journal of Immunology

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Murine CD4+CD25+ T regulatory (Treg) cells were cocultured with CD4+CD25− Th cells and APCs or purified B cells and stimulated by anti-CD3 mAb. Replacement of APCs by B cells did not significantly affect the suppression of CD4+CD25− Th cells. When IL-4 was added to separate cell populations, this cytokine promoted CD4+CD25− Th and CD4+CD25+ Treg cell proliferation, whereas the suppressive competence of CD4+CD25+ Treg cells was preserved. Conversely, IL-4 added to coculture of APCs, CD4+CD25− Th cells, and CD4+CD25+ Treg cells inhibited the suppression of CD4+CD25− Th cells by favoring their survival through the induction of Bcl-2 expression. At variance, suppression was not affected by addition of IL-13, although this cytokine shares with IL-4 a receptor chain. When naive CD4+CD25− Th cells were replaced by Th1 and Th2 cells, cell proliferation of both subsets was equally suppressed, but suppression was less pronounced compared with that of CD4+CD25− Th cells. IL-4 production by Th2 cells was also inhibited. These results indicate that although CD4+CD25+ Treg cells inhibit IL-4 production, the addition of IL-4 counteracts CD4+CD25+ Treg cell-mediated suppression by promoting CD4+CD25− Th cell survival and proliferation.

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Cytotoxic T lymphocyte‐associated antigen‐4 inhibits integrin‐mediated stimulation

Cited by 15 publications

References 43 publications

Blockade of cytotoxic T-lymphocyte antigen-4 as a new therapeutic approach for advanced melanoma

Blockade of cytotoxic T-lymphocyte antigen-4 as a new therapeutic approach for advanced melanoma

Regulation of the Small GTPase Rap1 and Extracellular Signal-Regulated Kinases by the Costimulatory Molecule CTLA-4

IL-4 Modulation of CD4+CD25+ T Regulatory Cell-Mediated Suppression

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