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and Expression of the TCR/CD3 Complex at the Cell Surface1
*
The Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, and
Bone and Joint Research Unit, St. Bartholomew’s and Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, London, United Kingdom
A role for TNF-
in the pathogenesis of chronic inflammatory
disease is now firmly established. Paradoxically, TNF also has potent
immunomodulatory effects on CD4+ T lymphocytes, because
Ag-specific proliferative and cytokine responses are suppressed
following prolonged exposure to TNF. We explored whether TNF attenuated
T cell activation by uncoupling proximal TCR signal transduction
pathways using a mouse T cell hybridoma model. Chronic TNF exposure
induced profound, but reversible, T cell hyporesponsiveness, with
TNF-treated T cells requiring TCR engagement with higher peptide
concentrations for longer periods of time for commitment to IL-2
production. Subsequent experiments revealed that chronic TNF exposure
led to a reversible loss of TCR
chain expression, in part through a
reduction in gene transcription. Down-regulation of TCR expression
impaired TCR/CD3 assembly and expression at the cell surface and
uncoupled membrane-proximal tyrosine phosphorylation events, including
phosphorylation of the TCR chain itself, CD3
, ZAP-70 protein
tyrosine kinase, and linker for activation of T cells (LAT).
Intracellular Ca2+ mobilization was also suppressed in
TNF-treated T cells. We propose that TNF may contribute to T cell
hyporesponsiveness in chronic inflammatory and infectious diseases by
mechanisms that include down-regulation of TCR expression. We
speculate that by uncoupling proximal TCR signals TNF could also
interrupt mechanisms of peripheral tolerance that are dependent upon
intact TCR signal transduction pathways.
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