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  • Review Article
  • Published:

TCR ζ-chain downregulation: curtailing an excessive inflammatory immune response

Key Points

  • The T-cell receptor (TCR) functions in antigen recognition and signal transduction, which are two crucial steps in the initiation of an antigen-specific immune response. Of the TCR subunits, the ζ-chain has an important role in receptor assembly, expression and signalling.

  • Downregulation of the expression of the ζ-chain and impairment of T-cell function occur in T cells that have been isolated from patients with various pathologies, such as cancer, infections and autoimmune diseases. This occurs under conditions of sustained exposure to antigen and chronic inflammation, and it affects all T cells, including those not involved in triggering the specific immune response.

  • Interferon-γ has an important role in the induction of this phenomenon by recruiting and/or activating regulatory myeloid suppressor cells (MSCs) to lymphatic organs. During chronic inflammation, these cells create an immunosuppressive environment, leading to the downregulation of ζ-chain expression by T cells and natural killer cells and affecting cell differentiation and/or proliferation, and cytokine secretion.

  • Cumulative data indicate that downregulation of ζ-chain expression and impairment of T-cell function are normal responses of the immune system, which have evolved to attenuate T-cell function and to overcome the exacerbated activation that occurs in a developing chronic inflammatory environment.

  • This phenomenon has a major impact on current immunotherapies, because an immunosuppressive environment might obstruct the efficacy of vaccinations and T-cell therapies.

  • ζ-chain expression levels could be used as a prognostic marker for the presence of an immunosuppressive environment and for measuring the impact of the pathology on the immune system of the patient. If downregulation of ζ-chain expression is detected in a patient, agents that restore normal immune function must be administered before, or in conjunction with, the immunotherapy. Blockade of negative regulatory pathways might be required to potentiate the effect of any immunotherapies used.

Abstract

The T-cell receptor (TCR) functions in both antigen recognition and signal transduction, which are crucial initial steps of antigen-specific immune responses. TCR integrity is vital for the induction of optimal and efficient immune responses, including the routine elimination of invading pathogens and the elimination of modified cells and molecules. Of the TCR subunits, the ζ-chain has a key role in receptor assembly, expression and signalling. Downregulation of TCR ζ-chain expression and impairment of T-cell function have been shown for T cells isolated from hosts with various chronic pathologies, including cancer, and autoimmune and infectious diseases. This review summarizes studies of the various pathologies that show this phenomenon and provides new insights into the mechanism responsible for downregulation of ζ-chain expression, its relevance and its clinical implications.

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Figure 1: Activation and attenuation signals controlling TCR-mediated T-cell function.
Figure 2: ζ-chain structure and interactions in T cells and NK cells.
Figure 3: ζ-chain expression in acute and chronic inflammation.

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Acknowledgements

I gratefully acknowledge the support of the Society of Research Associates of the Lautenberg Center, New York, United States, the Concern Foundation of Los Angeles, United States, and the Harold B. Abramson Chair in Immunology, Jerusalem, Israel. This study was supported by The Israel Academy of Sciences and Humanities, and by The Joseph and Matilda Melnick fund Houston, United States. I thank S. Caplan, S. Schwarzbaum, L. Cohen-Daniel, E. Manaster and I. Vaknin for careful reading of the manuscript and constructive suggestions.

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DATABASES

Entrez Gene

arginase-1

caspase-3

CD3γ

CD3δ

CD3ε

CD16

FcεRγ

FYN

GM-CSF

GR1

granzyme B

IFN-γ

inducible NO synthase

LCK

NKp30

NKp46

TNF

ZAP70

ζ-chain

Infectious Disease Information

AIDS

leprosy

OMIM

rheumatoid arthritis

SLE

Glossary

CBL

A 120-kDa protein that functions as a RING-type E3 ubiquitin ligase. CBL targets the T-cell receptor–CD3 complex for ubiquitin conjugation, through the tyrosine kinase ZAP70 (ζ-chain-associated protein kinase of 70 kDa). In addition to proteasome- and lysosome-mediated degradation, ubiquitylation affects diverse biological processes, such as receptor downmodulation, signal transduction, protein processing and translocation, protein–protein interactions and gene transcription.

IMMUNORECEPTOR TYROSINE-BASED ACTIVATION MOTIFS

(ITAMs). Regions in the cytoplasmic domains of the invariant chains that are part of various cell-surface immune receptors, such as the T-cell receptor, the B-cell receptor, the receptor for IgE (FcεR) and natural-killer-cell activating receptors. Following phosphorylation, the ITAMs function as docking sites for SRC homology 2 (SH2)-domain-containing tyrosine kinases and adaptor molecules, thereby facilitating intracellular signalling casacdes.

SYSTEMIC LUPUS ERYTHEMATOSUS

(SLE). An autoimmune disease in which autoantibodies specific for DNA, RNA or proteins associated with nucleic acids form immune complexes that damage small blood vessels, especially in the kidney. Despite extensive study, this disease is still not fully understood and differs from other autoimmune diseases in several respects.

SYNOVIAL FLUID

The fluid that accumulates in the joints of patients with rheumatoid arthritis, which is a common inflammatory joint disease that has a strong autoimmune component.

MYELOID SUPPRESSOR CELLS

(MSCs). A population of cells composed of mature and immature myeloid cells. They are generated and/or activated during an inflammatory immune response. Through direct interactions and secreted components, they negatively affect T cells, which leads to the downregulation of ζ-chain expression and impairment of T-cell function.

TLR LIGANDS

A group of pathogen-associated molecular patterns — such as lipopolysaccharide, CpG-motif-containing DNA, double-stranded RNA and flagellin — that activate Toll-like receptors (TLRs). TLRs are expressed mainly by cells of the innate immune system (such as macrophages, dendritic cells and natural killer cells) and are also expressed by some cells of the adaptive immune system (T cells and B cells). Endogenous mammalian proteins — such as heat-shock proteins, DNA and extracellular-matrix components — which are characteristic of damaged tissues and typical of necrotic tumours, metastases, autoimmune diseases and infections, could also activate TLRs. TLRs and their various ligands have an important role in the excessive generation and/or activation of myeloid suppressor cells and in the induction of a chronic inflammatory immune response.

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Baniyash, M. TCR ζ-chain downregulation: curtailing an excessive inflammatory immune response. Nat Rev Immunol 4, 675–687 (2004). https://doi.org/10.1038/nri1434

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