Alterations in the expression of signal-transducing CD3ζ chain in T cells from patients with chronic inflammatory/autoimmune diseases

“…Ligation of the TCR with its cognate peptide-MHC-II ligand expressed on APC results in the rapid phosphorylation of tyrosine residues within the tyrosine-based activation motifs of the CD3 chain by the Src family kinases p56 LCK and p59 FYN . These biochemical events ultimately result in the activation of transcription factors that translocate to the nucleus to initiate cytokine gene transcription, lymphocyte proliferation, and effector responses (10,13,64).Transcription factors that participate in inducing cytokine synthesis in T cells include AP-1, NF-AT, and NF-B (71). Although these transcription factors all contribute to the activation of human T cells, NF-B is essential in initiating the transcriptional response to TCR and CD28 ligation, expression of IL-2, and proliferation (29,40,44,49).…”

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confidence: 99%

“…A key event in the induction of CD4 ϩ T-cell responses is the stimulation of the T-cell receptor (TCR)/CD3 complex on the membranes of T cells by major histocompatibility complex class II (MHC-II) molecule-peptide conjugates (13). The TCR/CD3 complex consists of six distinct chains.…”

mentioning

confidence: 99%

Low Levels of NF-κB/p65 Mark Anergic CD4⁺T Cells and Correlate with Disease Severity in Sarcoidosis

Lee

Barber

Kanchwala

et al. 2011

Clin Vaccine Immunol

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T lymphocytes from patients with sarcoidosis respond weakly when stimulated with mitogen or antigen. However, the mechanisms responsible for this anergy are not fully understood. Here, we investigated the protein levels of nuclear transcription factor NF-B (p50, p65, and p105), IB␣ (inhibitor of NF-B), T-cell receptor (TCR) CD3-chain, tyrosine kinase p56 LCK , and nuclear factor of activated T cells c2 (NF-ATc2) in peripheral blood CD4 ؉ T cells from patients with sarcoidosis. Baseline expression of p65 in these lymphocytes was reduced in 50% of patients. The reduced levels of p65 in sarcoid CD4؉ T cells concurred with decreased levels of p50, p105, CD3, p56 LCK , IB␣, and NF-ATc2. Polyclonal stimulation of NF-B-deficient sarcoid T cells resulted in reduced expression of CD69 and CD154, decreased proliferation, and cytokine (i.e., interleukin 2 [IL-2] and gamma interferon [IFN-␥]) production. The clinical significance of these findings is suggested by the association between low p65 levels and the development of more severe and active sarcoidosis. Although correlative, our results support a model in which multiple intrinsic signaling defects contribute to peripheral T-cell anergy and the persistence of chronic inflammation in sarcoidosis.Sarcoidosis is a multisystem disease of unknown etiology characterized by noncaseating granuloma formation (15,32). It is associated with anergic responses to skin tests and depressed peripheral T-lymphocyte responses in vitro (16,34). Several studies have examined the mechanisms of peripheral anergy in sarcoidosis. Early reports concluded that the T-cell anergy in sarcoidosis patients was partly due to a decreased production of interleukin 1 (IL-1) by monocytes (28). It was also shown that monocytes contributed to the suppressed lymphocyte responses by releasing increased amounts of prostaglandins (24). More recently, it was demonstrated that expansion of regulatory T cells (Treg cells) and diminished dendritic cell function could be responsible for the peripheral T-cell anergy observed with sarcoidosis. The proposed mechanisms implicated in this suppression included inhibition of IL-2 production and T-cell proliferation by Treg cells and a decreased ability of myeloid dendritic cells to stimulate T lymphocytes (46, 50). Sarcoid patients, however, do not appear to develop significant clinical evidence of immunosuppression, as they are capable of mounting effective immune responses to bacterial, fungal, and viral infections (70). Compartmentalization of these effective responses to the affected organs (i.e., lungs) could also explain the peripheral anergy associated with this disease (30, 31). Although the T-cell anergy associated with sarcoidosis was recognized long ago, the underlying mechanism and implications of this phenomenon for the pathogenesis of sarcoidosis remain unclear.A key event in the induction of CD4 ϩ T-cell responses is the stimulation of the T-cell receptor (TCR)/CD3 complex on the membranes of T cells by major histocompatibility complex class II (MHC-II) mol...

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“…Downregulation of CD3z-chain and decreased responsiveness of T cells were observed in some systemic autoimmune diseases (12,17). We investigated the potential impact of z-chain downregulation on activation-induced IL-2 production.…”

Section: Downregulation Of Z-chain Following Tnf Treatment Is Associamentioning

confidence: 99%

“…The TCR/CD3 complex is degraded in the lysosomes and proteasomes (8,11). Downregulation of the CD3z has been reported both in rheumatoid arthritis (RA) and in systemic lupus erythematosus (SLE) (12). In RA, decreased CD3z-chain expression of synovial fluid and peripheral T lymphocytes (13) is associated with suppressed proliferative capacity and altered cytokine production (14,15).…”

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confidence: 99%

CD3ζ-Chain Expression of Human T Lymphocytes Is Regulated by TNF via Src-like Adaptor Protein-Dependent Proteasomal Degradation

Érsek

Molnár

Balogh

et al. 2012

The Journal of Immunology

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Decreased expression of the TCR ζ-chain has been reported in several autoimmune, inflammatory, and malignant diseases, suggesting that ζ-chain downregulation is common at sites of chronic inflammation. Although ζ-chain is critically important in T lymphocyte activation, the mechanism of the decreased ζ-chain expression is less clear. Src-like adaptor protein (SLAP) is a master regulator of T cell activation; previous data have reported that SLAP regulates immunoreceptor signaling. We have examined the mechanism and the functional consequences of CD3 ζ-chain downregulation. TNF treatment of human T lymphocytes (15–40 ng/ml) selectively downregulates CD3 ζ-chain expression in a dose-dependent manner (p < 0.05) and decreases activation-induced IL-2 expression (p < 0.01). Although blocking of the lysosomal compartment fails to restore TNF-induced CD3 ζ-chain downregulation, inhibition of the proteasome prevented the effect of TNF. Both SLAP expression and the colocalization of SLAP with CD3 ζ-chain was enhanced by TNF treatment (p < 0.05 and p < 0.01, respectively), whereas TNF-induced ζ-chain downregulation was inhibited by gene silencing of SLAP with small interfering RNA. SLAP levels of the CD4+ T lymphocytes isolated from patients with rheumatoid arthritis were more than 2-fold higher than that of the healthy donors’ (p < 0.05); moreover, TNF treatment did not alter the SLAP expression of the CD4+ cells of anti-TNF therapy-treated patients. Our present data suggest that TNF modulates T cell activation during inflammatory processes by regulating the amount of CD3 ζ-chain expression via a SLAP-dependent mechanism. These data provide evidence for SLAP-dependent regulation of CD3 ζ-chain in the fine control of TCR signaling.

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Alterations in the expression of signal-transducing CD3ζ chain in T cells from patients with chronic inflammatory/autoimmune diseases

Cited by 20 publications

References 107 publications

Variation in the Cd3ζ (Cd247) Gene Correlates with Altered T Cell Activation and Is Associated with Autoimmune Diabetes

Variation in the Cd3ζ (Cd247) Gene Correlates with Altered T Cell Activation and Is Associated with Autoimmune Diabetes

Low Levels of NF-κB/p65 Mark Anergic CD4⁺T Cells and Correlate with Disease Severity in Sarcoidosis

CD3ζ-Chain Expression of Human T Lymphocytes Is Regulated by TNF via Src-like Adaptor Protein-Dependent Proteasomal Degradation

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Alterations in the expression of signal-transducing CD3ζ chain in T cells from patients with chronic inflammatory/autoimmune diseases

Cited by 20 publications

References 107 publications

Variation in the Cd3ζ (Cd247) Gene Correlates with Altered T Cell Activation and Is Associated with Autoimmune Diabetes

Variation in the Cd3ζ (Cd247) Gene Correlates with Altered T Cell Activation and Is Associated with Autoimmune Diabetes

Low Levels of NF-κB/p65 Mark Anergic CD4+T Cells and Correlate with Disease Severity in Sarcoidosis

CD3ζ-Chain Expression of Human T Lymphocytes Is Regulated by TNF via Src-like Adaptor Protein-Dependent Proteasomal Degradation

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Low Levels of NF-κB/p65 Mark Anergic CD4⁺T Cells and Correlate with Disease Severity in Sarcoidosis