CTLA-4 Overexpression Inhibits T Cell Responses through a CD28-B7-Dependent Mechanism

Engelhardt, John J.; Sullivan, Timothy J.; Allison, James P.

doi:10.4049/jimmunol.177.2.1052

Cited by 117 publications

(83 citation statements)

References 52 publications

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“…Calcineurin inhibition affects the same group of genes as CD28 inhibition and to nearly the same degree, suggesting that reducing nuclear export of NFAT is an important functional consequence of CD28 signaling. CD28 stimulation is opposed by CTLA-4 (12,13) and CTLA-4-deficient mice develop a fatal lymphoproliferative disorder, underscoring the importance of proper costimulation regulation in maintaining immune homeostasis (14,15).…”

mentioning

confidence: 99%

Enhanced NFATc1 Nuclear Occupancy Causes T Cell Activation Independent of CD28 Costimulation

Pan¹,

Winslow²,

Chen

et al. 2007

The Journal of Immunology

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TCR signals induce the nuclear localization of NFATc proteins, which are removed from the nucleus after rephosphorylation by glycogen synthase kinase 3 and other kinases. Rapid nuclear export might allow continuous monitoring of receptor occupancy, making the transcriptional response proportional to the duration of TCR/CD28 signaling. To investigate this possibility, we analyzed mice in which T cells express a NFATc1 variant (NFATc1 nuc ) with serine-to-alanine changes at the glycogen synthase kinase 3 phosphorylation sites. NFATc1 nuc T cells have constitutively nuclear NFATc1, enhanced T cell activation in vivo, and calcineurin-independent proliferation in vitro. NFATc1 nuc T cells are hypersensitive to TCR/CD3 stimulation, resulting in enhanced proliferation and cytokine production that is independent of CD28 costimulation. These results support the notion that CD28 inhibits nuclear export of NFATc transcription factors. In addition, NFATc1 nuc destabilizes a positive feedback loop in which NFATc1 activates its own transcription as well as its targets, such as CD40 ligand and Th1/Th2 cytokines. The Journal of Immunology, 2007, 178: 4315-4321. Maximal and sustained activation of T lymphocytes requires integration of the signaling pathways downstream of the TCR and of coreceptors such as CD28 (1). Stimulation of naive T lymphocytes through their TCR in the presence of costimulation results in activation and proliferation while TCR stimulation alone can result in anergy or cell death. TCR stimulation activates the Ca 2ϩ /calcineurin-regulated calcineurin phosphatase complex. Calcineurin dephosphorylates and activates the NFATc family of transcription factors, the activation of which is required in T cells for the induction of antigenic and tolerogenic genetic programs (2). Concurrent CD28 costimulation of CD4 ϩ helper T cells results in the induction of genes that regulate cell cycle entry and promote survival as well as the expression of cell surface and secreted molecules that coordinate the immune response (3). The signaling pathways regulated by CD28 are controversial, but substantial evidence indicates that glycogen synthase kinase 3 (GSK3) 3 is inhibited by CD28, perhaps through a pathway involving PI3K and AKT (4, 5). GSK3 is also an important regulator of WNT signaling and apoptosis and plays critical roles in many biological systems (6).Genome-wide gene expression profiling indicates that one important aspect of CD28 signaling is the inhibition of GSK3, resulting in reduced nuclear export of nuclear NFATc proteins (7). Normally, nuclear export occurs when Dyrk1a and/or protein kinase A in the nucleus phosphorylate the serine/proline repeats and serine-rich region in the N termini of NFATc proteins (8). This primes NFAT for sequential phosphorylation by GSK3 (9 -12). Calcineurin inhibition affects the same group of genes as CD28 inhibition and to nearly the same degree, suggesting that reducing nuclear export of NFAT is an important functional consequence of CD28 signaling. CD28 stimulation is opposed by...

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mentioning

confidence: 99%

Enhanced NFATc1 Nuclear Occupancy Causes T Cell Activation Independent of CD28 Costimulation

Pan¹,

Winslow²,

Chen

et al. 2007

The Journal of Immunology

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“…Autoimmune diseases developed in CTLA-4-deficient mice provide compelling evidence to demonstrate the crucial inhibitory role of CTLA-4, which results from accumulation of T cell blasts in spleen and LN, and depleting T cells in CTLA-4 deficient mice prevents these diseases. Consistently, CTLA-4 overexpression on cell surface impairs T-cell responses in vivo and in vitro as shown in CTLA-4 transgenic mice [28].…”

Section: Function and Cellular Trafficking Of Ctla-4mentioning

confidence: 63%

PD-1 and CTLA-4 Mediated Inhibitory Signaling for T cell Exhaustion during Chronic Viral Infections

Li¹,

Xu²,

Wang³

et al. 2013

J Clin Cell Immunol

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Emerging studies show that T cell exhaustion correlates well with increased expression levels of inhibitory receptors including Programmed cell death receptor 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) during chronic infections. Both inhibitory molecules play similar but non-redundant role in T cell exhaustion. Engagement of PD-1 and CTLA-4 by their ligands inhibits T cell proliferation, cytokine secretion, and attenuates immune responses. Blockade of PD-1 and CTLA-4 restores effector function of exhausted T cells. PD-1 and CTLA-4 could both recruit Src homology 2-containing tyrosine phosphatase 2 (SHP2) and inhibit activation of Akt. Nevertheless, PD-1 and CTLA-4 also target distinct signaling molecules to inhibit T cell function. In this review, we will discuss current understanding of PD-1 and CTLA-4 initiated signaling pathways, their regulatory roles in a variety of chronic viral infections, and their promising potential as targets to enhance T cell function for antiviral therapy.

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“…12,13 The CTLA4 gene produces two different isoforms: a full-length CTLA4 (flCTLA4) protein, encoded by exon 1 (peptide leader), exon 2 (extracellular domain), exon 3 (transmembrane domain) and exon 4 (cytoplasmic domain), as well as a soluble CTLA4 (sCTLA4) protein in which exon 3 is lost. The flCTLA4 protein is expressed mainly in activated T cells, whereas the sCTLA4 protein is secreted mainly by resting T cells, and sCTLA4 mRNA expression is downregulated after activation.…”

Section: Introductionmentioning

confidence: 99%

“…17 Hence, CTLA4 is involved in resistance to the inflammatory response, and it has been suggested that CTLA4, which is an important negative regulator of T cells, might be implicated in the pathogenesis of T-cell-mediated UC. 11,13 CTLA4 is involved in susceptibility to autoimmune diseases. 18,19 Several single-nucleotide polymorphisms have been associated with autoimmune diseases such as type I diabetes, Graves' disease (GD) and multiple sclerosis; however, some of these associations have not been confirmed, and there are even some contradictory data in different populations.…”

Section: Introductionmentioning

confidence: 99%

CTLA4 −1661A/G and 3′UTR long repeat polymorphisms are associated with ulcerative colitis and influence CTLA4 mRNA and protein expression

Chen

Brant

et al. 2010

Genes Immun

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Reduced cytotoxic T-lymphocyte antigen 4 (CTLA4) expression has been proposed as a risk for autoimmunity. CTLA4 polymorphisms have been associated with several autoimmune diseases, including ulcerative colitis (UC). In this study, we performed genotyping for CTLA4 À1661A/G, À1722T/C and 3 0 untranslated region (AT)n repeat polymorphisms in 300 Chinese UC patients and in 700 healthy controls, and evaluated the effects of polymorphisms on full-length (flCTLA4) and soluble CTLA4 (sCTLA4) expression in UC patients. The frequency of the À1661G allele was higher in UC patients than in healthy controls (16.5 vs 11.4%, P ¼ 0.003, odds ratio (OR) ¼ 1.53, 95% confidence interval (95% CI): 1.17-2.01). The prevalence of (AT)n repeats of the CTLA4 gene carrying long alleles (X116 bp) was more common in UC patients than in healthy controls (22.0 vs 6.3%, Po0.001, OR ¼ 4.21, 95% CI: 2.79-6.33), and was associated with extensive colitis (P ¼ 0.008). Among UC patients, long-allele carriers expressed lower levels of flCTLA4 and sCTLA4 mRNA and sCTLA4 protein than did short-allele carriers (Po0.001, Po0.001, Po0.001, respectively). CTLA4 gene À1661A/G and long 3 0 untranslated region (AT)n repeat polymorphisms are associated with UC in Central China. This is likely from decreased expressions of sCTLA4 mRNA and sCTLA4 protein. Our study suggests that CTLA4 has an important role in susceptibility for UC in Central China.

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CTLA-4 Overexpression Inhibits T Cell Responses through a CD28-B7-Dependent Mechanism

Cited by 117 publications

References 52 publications

Enhanced NFATc1 Nuclear Occupancy Causes T Cell Activation Independent of CD28 Costimulation

Enhanced NFATc1 Nuclear Occupancy Causes T Cell Activation Independent of CD28 Costimulation

PD-1 and CTLA-4 Mediated Inhibitory Signaling for T cell Exhaustion during Chronic Viral Infections

CTLA4 −1661A/G and 3′UTR long repeat polymorphisms are associated with ulcerative colitis and influence CTLA4 mRNA and protein expression

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