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

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 zeta-chain has a key role in receptor assembly, expression and signalling. Downregulation of TCR zeta-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 zeta-chain expression, its relevance and its clinical implications.

Natural killer cells phenotypic characterization as an outcome predictor of HCV-linked HCC after curative treatments

“…Diminished CD3z expression or function has been observed in T and NK-cells from patients with infections, auto-immune diseases and cancer. 19,20 The loss of CD3z function is, therefore, a likely cause of reduced NKp46-p30 signaling capacity and a potential predictor of poor prognosis and survival, 20 consistent with our observation of significantly decreased CD3z expression in HCC patients with worse outcome.…”

A reversed CD4/CD8 ratio of tumor-infiltrating lymphocytes and a high percentage of CD4+FOXP3+ regulatory T cells are significantly associated with clinical outcome in squamous cell carcinoma of the cervix

“…More importantly, the similarity of the two cytotoxic markers (GrB and Prf) reflects that the cytotoxic machinery of the infiltrates was intact, suggesting that the dysfunctional status of the effector cells was due to the influence of the microenvironment 39 rather than to the physical dysfunction of signal transduction in the T cells. 40 Thus, the low expression of the T-cell receptor-f chain, the T cell-signaling molecule, observed in CD8 1 TILs of cervical cancer patients, may not be associated with chronic viral infection. 39 Interestingly, these results differ from our previous data regarding breast cancer, which revealed a significant discrepancy in the numbers of GrB-and Prf-positive cells.…”

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

“…The molecular mechanisms responsible for the defective expression of CD3z in these diseases are diverse (reviewed in Refs. 23,38).…”

“…In humans, a defective expression of the CD3z-chain has been associated with autoimmune diseases, including systemic lupus erythematosus (SLE) (19,20) and rheumatoid arthritis (21,22), with T cells from these patients displaying a functional impairment. Together, these data suggest that downregulation of CD3z has functional consequences in systemic autoimmunity (23,24). This also agrees with the notion that the strength of the TCR signal is critical for cell lineage fate in T cell development (25), as well as in controlling autoimmunity (26).…”