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- Open Access
Does sustained downregulation of the TCRzeta chain define the transition from antigen mode to inflammation mode in effector T lymphocytes?
Arthritis Res Thervolume 5, Article number: 90 (2003)
The molecular events that define the early phase of activation and differentiation of effector T cells have been well characterized. Those events promoting the effector function of chronically activated T cells at sites of inflammation are less well understood. Using in vitro and in vivo models, we have explored the effects of the chronic inflammatory process on T-cell differentiation by studying the effects of tumor necrosis factor (TNF) on T-cell activation and effector responses. These studies have revealed that TNF-stimulated T cells resemble rheumatoid arthritis synovial T cells since they express cell surface activation antigens, but are profoundly hyporesponsive to T-cell receptor (TCR) engagement. This may be explained, at least in part, by the observation that TNF selectively targets the expression of the TCRzeta chain. Loss of TCRzeta expression perturbs the assembly, expression and stability of the TCR/CD3 complex, leading to attenuation of membrane proximal tyrosine phosphorylation, intracellular calcium mobilisation and the transcription of cytokine genes upon TCR engagement, when compared with untreated T cells.
We set out to explore whether TCRzeta expression could be used to identify chronically activated, hyporesponsive T cells in vivo. Using a FACS-based assay, we have identified subsets of CD3+ T cells expressing low levels of TCRzeta (hereafter termed TCRzetadim cells) in the peripheral blood of healthy donors, as well as patients with inflammatory arthritis. Subsequent experiments revealed that, when compared with TCRzetabright cells, the TCRzetadim population is enriched for cells expressing effector memory cell surface markers. By staining with HLA class I/peptide tetramer complexes, CD8+TCR-zetadim cells are enriched for antigen-specific T cells after stimulation in vitro with specific peptide. While TCRzetadim cells are hyporesponsive to TCR engagement, they retain effector potential, since a significant proportion are TNF-α and IFN-γ producers upon stimulation with phorbol ester and calcium ionophore. In contrast, fewer produce IL-10 when compared with the TCRzetabright subset. These data suggest that TCRzetadim T cells, which are abundant at sites of inflammation, may represent a subset of circulating antigen experienced effector memory cells. Sustained downregulation of TCRzeta may define a checkpoint where the intracellular signals driving T-cell differentiation switch from antigen mode to inflammation mode.
This work was funded by the Wellcome Trust UK, and the Arthritis Research Campaign.