CTLA-4 Suppresses Proximal TCR Signaling in Resting Human CD4+ T Cells by Inhibiting ZAP-70 Tyr319 Phosphorylation: A Potential Role for Tyrosine Phosphatases

Guntermann, Christine; Alexander, Denis R.

doi:10.4049/jimmunol.168.9.4420

Cited by 115 publications

(69 citation statements)

References 43 publications

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“…This agrees with reports that SHP-1 does not dephosphorylate the TCR or BCR ITAMs (16,26,27). Yet, several reports have suggested that SHP-1 can dephosphorylate ITAMs.…”

Section: Discussionsupporting

confidence: 82%

PTPH1 Is a Predominant Protein-tyrosine Phosphatase Capable of Interacting with and Dephosphorylating the T Cell Receptor ζ Subunit

Sozio

Mathis

Young

et al. 2004

Journal of Biological Chemistry

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Protein-tyrosine phosphatases (PTPases) play key roles in regulating tyrosine phosphorylation levels in cells, yet the identity of their substrates remains limited. We report here on the identification of PTPases capable of dephosphorylating the phosphorylated immune tyrosine-based activation motifs present in the T cell receptor subunit. To characterize these PTPases, we purified enzyme activities directed against the phosphorylated T cell receptor subunit by a combination of anion and cation chromatography procedures. A novel ELISA-based PTPase assay was developed to rapidly screen protein fractions for enzyme activity following the various chromatography steps. We present data that SHP-1 and PTPH1 are present in highly enriched protein fractions that exhibit PTPase activities toward a tyrosine-phosphorylated TCR substrate (specific activity ranging from 0.23 to 40 pmol/min/g). We also used a protein-tyrosine phosphatase substrate-trapping library comprising the catalytic domains of 47 distinct protein-tyrosine phosphatases, representing almost all the tyrosine phosphatases identified in the human genome. PTPH1 was the predominant phosphatase capable of complexing phospho-. Subsequent transfection assays indicated that SHP-1 and PTPH1 are the two principal PTPases capable of regulating the phosphorylation state of the TCR ITAMs, with PTPH1 directly dephosphorylating . This is the first reported demonstration that PTPH1 is a candidate PTPase capable of interacting with and dephosphorylating TCR .The T and B cell antigen receptors contain multiple copies of an immune tyrosine-based activation motif (ITAMs), 1 which initiate intracellular signals by coupling to several families of protein-tyrosine kinases (PTKs) (1). The activation of this pathway following receptor-ligand interactions results in a transient accumulation of tyrosine-phosphorylated proteins, leading to the induction of cellular effector functions (2, 3). Following TCR engagement, two tyrosine residues within each ITAM are specifically phosphorylated by the Src family of PTKs (2, 4). Once bi-phosphorylated, the ITAMs serve as high affinity binding sites for the ZAP-70/Syk family of PTKs, with each of two Src homology 2 (SH2) domains of Syk/ZAP-70 binding to one of the two phospho-tyrosine sequences (5, 6). The ␣␤ T cell receptor (TCR) complex actually comprises up to ten ITAMs that are distributed among the TCR and CD3 ␥, ␦, and ⑀ subunits (3). The presence of ten ITAMs is proposed to support signal amplification and/or signal bifurcation (reviewed in Refs. 3 and 4). 6 of 10 ITAMs in the TCR complex are localized in the TCR homodimer (three per chain), facilitating the recruitment of multiple ZAP-70 molecules following ITAM phosphorylations (3,7,8). There are two predominant tyrosinephosphorylated forms of that migrate with distinct molecular masses of 21 and 23 kDa, and their differential induction are linked to multiple critical biological functions for T cells (3, 8) (reviewed in Refs. 3,4,and 9).It is well established that intracellular protei...

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“…This agrees with reports that SHP-1 does not dephosphorylate the TCR or BCR ITAMs (16,26,27). Yet, several reports have suggested that SHP-1 can dephosphorylate ITAMs.…”

Section: Discussionsupporting

confidence: 82%

PTPH1 Is a Predominant Protein-tyrosine Phosphatase Capable of Interacting with and Dephosphorylating the T Cell Receptor ζ Subunit

Sozio

Mathis

Young

et al. 2004

Journal of Biological Chemistry

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“…The exact mechanisms by which CTLA-4 is able to inhibit T-cell activation have been studied extensively; cross-linking CTLA-4 in the context of CD3/CD28 stimulation has been shown to inhibit T-cell proliferation via interaction with proximal intracellular signalling molecules such as TCR-z [7,64,65]. We show here that CTLA-4 fails to regulate proximal T-cell signalling and T-cell proliferation in lupus patients.…”

Section: Discussionmentioning

confidence: 76%

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

et al. 2010

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CTLA‐4 is a critical gatekeeper of T‐cell activation and immunological tolerance and has been implicated in patients with a variety of autoimmune diseases through genetic association. Since T cells from patients with the autoimmune disease systemic lupus erythematosus (SLE) display a characteristic hyperactive phenotype, we investigated the function of CTLA‐4 in SLE. Our results reveal increased CTLA‐4 expression in FOXP3− responder T cells from patients with SLE compared with other autoimmune rheumatic diseases and healthy controls. However, CTLA‐4 was unable to regulate T‐cell proliferation, lipid microdomain formation and phosphorylation of TCR‐ζ following CD3/CD28 co‐stimulation, in contrast to healthy T cells. Although lupus T cells responded in vitro to CD3/CD28 co‐stimulation, there was no parallel increase in CTLA‐4 expression, which would normally provide a break on T‐cell proliferation. These defects were associated with exclusion of CTLA‐4 from lipid microdomains providing an anatomical basis for its loss of function. Collectively our data identify CTLA‐4 dysfunction as a potential cause for abnormal T‐cell activation in patients with SLE, which could be targeted for therapy.

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“…The most well studied examples of such coreceptors are the CD28/CTLA-4 family members (3,4). Additional regulatory molecules that function as T cell coactivating or coinhibitory receptors have been described (2).…”

mentioning

confidence: 99%

Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Inhibits Proximal TCR Signaling by Targeting ZAP-70

Chen

Qiao

et al. 2008

The Journal of Immunology

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The long cytoplasmic tail (CT) isoforms of carcinoembryonic Ag-related cell adhesion molecule 1 (CEACAM1) are expressed on activated human T cells and possess two ITIM motifs in the CT. These isoforms of CEACAM1 are inhibitory for T cell responses initiated by the TCR/CD3 complex with the inhibition dependent upon the ITIMs of CEACAM1 and Src homology 2 domain-containing phosphatase 1 (SHP-1). However, the mechanism by which this inhibition occurs in T cells is unknown. We demonstrate here that the Src family kinase, Lck, and the ability of CEACAM1 to bind homophilically are required for the ITIM phosphorylation of CEACAM1 that is a prerequisite for CEACAM1 association with SHP-1. We further show that CEACAM1 associates with and recruits SHP-1 to the TCR/CD3 complex leading to decreased phosphorylation of CD3-ζ and ZAP-70 and consequently decreased activation of the elements downstream of ZAP-70. This is physiologically relevant because extinction of SHP-1 expression or blockade of homophilic binding by CEACAM1 using a Fab that specifically recognizes the homophilic binding region of human CEACAM1 increases the cytolytic function initiated by the TCR/CD3 complex. These studies show that long CT isoforms of CEACAM1 orchestrate an inhibitory program that abrogates extremely proximal events downstream of the TCR/CD3 complex by focusing on the activation of ZAP-70.

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CTLA-4 Suppresses Proximal TCR Signaling in Resting Human CD4+ T Cells by Inhibiting ZAP-70 Tyr319 Phosphorylation: A Potential Role for Tyrosine Phosphatases

Cited by 115 publications

References 43 publications

PTPH1 Is a Predominant Protein-tyrosine Phosphatase Capable of Interacting with and Dephosphorylating the T Cell Receptor ζ Subunit

PTPH1 Is a Predominant Protein-tyrosine Phosphatase Capable of Interacting with and Dephosphorylating the T Cell Receptor ζ Subunit

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Inhibits Proximal TCR Signaling by Targeting ZAP-70

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