Displacement of linker for activation of T cells from the plasma membrane due to redox balance alterations results in hyporesponsiveness of synovial fluid T lymphocytes in rheumatoid arthritis

The T lymphocytes that reside in the synovium of the inflamed joints in pat ients with rheumatoid arthritis display severe hyporesponsiveness upon anti genic stimulation, which is probably due to their constant subjection to hi gh levels of oxidative stress. Here we report that the synovial fluid T lym phocytes exert severely impaired phosphorylation of the adaptor protein lin ker for activation of T cells (LAT), a crucial component of the TCR-mediate d signaling pathways. In healthy T lymphocytes, LAT is a membrane-bound pro tein and becomes phosphorylated by zeta-associated protein of 70 kDa (ZAP-7 0) upon TCR engagement. The molecular basis underlying the deficient phosph orylation of LAT and consequently the hyporesponsiveness of the synovial fl uid T lymphocytes lies in the membrane displacement of LAT, We demonstrate that the subcellular localization of LAT is sensitive to changes in the int racellular levels of the antioxidant glutathione. The membrane anchorage of LAT, and consequently the phosphorylation of LAT and the cellular activati on of the synovial fluid T lymphocytes upon TCR engagement, is restored in synovial fluid T lymphocytes after supplementation of the intracellular glu tathione levels with N-acetyl-L-cysteine. These data suggest a role for the membrane displacement of LAT in the hyporesponsiveness of the synovial flu id T lymphocytes as a consequence of oxidative stress.