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Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
The T lymphocytes that reside in the synovium of the inflamed
joints in patients with rheumatoid arthritis display severe
hyporesponsiveness upon antigenic stimulation, which is probably due to
their constant subjection to high levels of oxidative stress. Here we
report that the synovial fluid T lymphocytes exert severely impaired
phosphorylation of the adaptor protein linker for activation of T cells
(LAT), a crucial component of the TCR-mediated signaling pathways. In
healthy T lymphocytes, LAT is a membrane-bound protein and becomes
phosphorylated by 
-associated protein of 70 kDa (ZAP-70) upon TCR
engagement. The molecular basis underlying the deficient
phosphorylation of LAT and consequently the hyporesponsiveness of the
synovial fluid T lymphocytes lies in the membrane displacement of LAT.
We demonstrate that the subcellular localization of LAT is sensitive to
changes in the intracellular levels of the antioxidant glutathione. The
membrane anchorage of LAT, and consequently the phosphorylation of LAT
and the cellular activation of the synovial fluid T lymphocytes upon
TCR engagement, is restored in synovial fluid T lymphocytes after
supplementation of the intracellular glutathione levels with
N-acetyl-L-cysteine. These data suggest a
role for the membrane displacement of LAT in the hyporesponsiveness of
the synovial fluid T lymphocytes as a consequence of oxidative
stress.
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