Cutting Edge: CTLA-4 (CD152) Differentially Regulates Mitogen-Activated Protein Kinases (Extracellular Signal-Regulated Kinase and c-Jun N-Terminal Kinase) in CD4+ T Cells from Receptor/Ligand-Deficient Mice

Schneider, Helga; Mandelbrot, Didier A.; Greenwald, Rebecca J.; Ng, Wan‐Fai; Lechler, Robert I.; Sharpe, Arlene H.; Rudd, Christopher E.

doi:10.4049/jimmunol.169.7.3475

Cited by 67 publications

(42 citation statements)

References 43 publications

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“…6) [5]. Moreover, previous reports indicated that CTLA-4/B7 engagement could inhibit extracellular signal-regulated kinases (ERK1 and ERK2) [45] thus protecting ICER from ERK-mediated phosphorylation and subsequent degradation by ubiquitination [46]. Therefore, contactdependent 'infectious' tolerance acting through ICER/ CREM-mediated inhibition of IL-2 synthesis could explain (i) how a relatively small population of T R cells effectively suppresses a much larger population of Foxp3 -responders, and (ii) how inducible CTLA-4 and B7 expression contributes to the spread of this infectious suppression conveyed by induction of ICER/CREM in antigen-nonspecific fashion (Fig.…”

Section: Discussionmentioning

confidence: 98%

ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

et al. 2007

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Here, we report that inducible cAMP early repressor/cAMP response element modulator (ICER/CREM) is induced early in CD25 + CD4 + regulatory T cell (T R ) assays mainly in activated Foxp3 -effector T cells and this induction correlates with sharp decrease in number of IL-2-expressing T cells. Importantly, RNAi targeting of ICER/CREM in responder CD25 -CD4 + T cells antagonizes T R -mediated suppression. Moreover, forced expression of Foxp3 in naive CD25 -T cells induces constitutive expression of ICER/ CREM in T cells with a regulatory phenotype. Foxp3 facilitates expression of ICER/ CREM both in Foxp3 transductants as well as CD25 -responder T cells suggesting that induction of T R function in suppression assays may utilize contact-dependent interaction. Indeed, CTLA-4 blockade or use of B7-deficient CD25 -responder T cells prevents ICER/CREM accumulation and leads to the rescue of IL-2 expression. Therefore, we propose that CTLA-4 binding to B7 ligands expressed on activated ligandbearing Foxp3 -effector T cells results in ICER/CREM-mediated transcriptional attenuation of IL-2. Collectively, these data suggest that Foxp3 expression in T R cells imposes suppression in contact-dependent fashion by induction of constitutive ICER/ CREM expression in activated CD25 + Foxp3 -T cell effectors thus preventing them from producing IL-2.

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Section: Discussionmentioning

confidence: 98%

ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

et al. 2007

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“…With subsequent increased expression of CTLA-4 on the surface of the T cell, the B7 and CTLA-4 interaction leads to a variety of intracellular signals resulting in reduction of TCR-mediated activation, including decreases in members of the mitogenactivated protein kinase pathway and c-Jun-NH 2 -kinase (ref. 7; Fig. 1B).…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic T-Lymphocyte–Associated Antigen-4

Salama¹,

Hodi²

2007

Clinical Cancer Research

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Previously, the development of immune-based therapies has primarily focused on vaccines and cytokines, yielding benefit in a small percentage of patients. Recent advances in our understanding of the function of costimulatory molecules have revitalized enthusiasm in the development of immune therapies for cancer. This family of proteins possesses properties involved in both lymphocyte activation and immune-inhibitory functions. The costimulatory molecule with the greatest translation into the clinic thus far is CTL-associated antigen-4 (CTLA-4). CTLA-4 engagement leads toT-cell inhibition by two principle mechanisms. The first involves competitive binding with CD28 for B7 on the antigen-presenting cell. The second is direct intracellular inhibitory signals mediated by the CTLA-4 cytoplasmic tail. Numerous clinical trials testing the blockade of CTLA-4 signaling with fully human monoclonal antibodies have treated a variety of cancers, with the most experience in the treatment of metastatic melanoma. Significant antitumor activity as well as potential autoimmune-related toxicities have been observed. Further clinical investigation with CTLA-4 blockade, planned clinical trials testing manipulation of other costimulatory molecules, and continued improvement in understanding of costimulatory pathways present a new era of immune therapies for cancer patients.

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“…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).…”

mentioning

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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Cutting Edge: CTLA-4 (CD152) Differentially Regulates Mitogen-Activated Protein Kinases (Extracellular Signal-Regulated Kinase and c-Jun N-Terminal Kinase) in CD4+ T Cells from Receptor/Ligand-Deficient Mice

Cited by 67 publications

References 43 publications

ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

Cytotoxic T-Lymphocyte–Associated Antigen-4

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

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