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Sustained downregulation of the TCRζ chain defines a transition from antigen mode to inflammation mode during terminal T-cell differentiation
Arthritis Research & Therapy volume 7, Article number: P76 (2005)
The molecular events that define early phases of activation and differentiation of effector T cells have been well characterised. Those events regulating terminal differentiation and effector function of chronically activated T cells at sites of inflammation, on the other hand, 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 investigating how tumour necrosis factor (TNF) regulates T-cell activation and effector responses. These studies have revealed that TNF-stimulated T cells resemble those derived from inflamed synovial joints since they express cell surface activation antigens, but are profoundly hyporesponsive to TCR engagement. Studies with mouse T cells suggest that this may be explained, at least in part, by the fact that TNF selectively targets the expression of the TCRζ chain. Loss of TCRζ 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 have begun to investigate whether TCRζ expression could be used as a 'bio-marker' for chronically activated, hyporesponsive T cells in human peripheral blood. Using a FACS-based assay, we have identified subsets of CD3+ T cells expressing low levels of TCRζ (hereafter termed TCRζdim cells) in the peripheral blood of healthy donors, as well as patients with inflammatory arthritis. In vitro studies of peripheral blood lymphocytes from healthy donors define not only antigen-dependent downmodulation of TCRζ expression, which is transient, but also more sustained downregulation, which may arise through antigen-independent mechanisms. Experiments reveal that, when compared with TCRζbright cells, the TCRζdim population is enriched for cells expressing effector memory cell surface markers. While TCRζdim cells are hyporesponsive to TCR engagement, they retain effector potential, since a significant proportion are capable of producing TNF-α and interferon gamma upon stimulation with phorbol ester and calcium ionophore. In contrast, the TCRζbright subset is enriched for IL-10 producers. Furthermore, TCRζdim T cells are capable of activating monocytes through cell contact-dependent mechanisms. Together these data suggested that TCRζdim T cells may represent a subset of circulating effector memory cells in vivo.
Finally, we observed that TCRζdim T cells are enriched in inflamed joints of patients with inflammatory synovitis. Treatment of rheumatoid arthritis patients with anti-TNF (infliximab, 3 mg/kg) leads to significant accumulation of TCRζdim T cells in peripheral blood of a subset of patients. Indeed, the extent of accumulation at 14 weeks after starting treatment predicts the DAS28 clinical response at 30 weeks. We propose that sustained downregulation of the TCRζ chain defines a checkpoint where intracellular signals driving T-cell differentiation and effector responses switch from antigen mode to inflammation mode, where effector function may be largely antigen independent. As such this cell subset may represent a valid therapeutic cellular target.
This work was funded by the Wellcome Trust and the Arthritis Research Campaign UK.
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Zhang, Z., Panesar, M., Amjadi, P. et al. Sustained downregulation of the TCRζ chain defines a transition from antigen mode to inflammation mode during terminal T-cell differentiation. Arthritis Res Ther 7, P76 (2005). https://doi.org/10.1186/ar1597
- Inflammation Mode
- Intracellular Calcium Mobilisation
- Effector Memory Cell
- Cell Surface Activation