Oxidized LAT and Hyporesponsiveness

Abstract

Correct localization to lipid rafts is essential for LAT (linker for activation of T cells)-mediated signaling through the T cell antigen receptor (TCR). Under conditions of chronic oxidative stress, T cells are hyporesponsive to stimuli. For example, in rheumatoid arthritis (RA), T cell insensitivity is thought to contribute to the disorder. Grinhuis et al . found that LAT localization in T cells is perturbed during chronic oxidative stress and results in decreased signaling outputs. LAT isolated from T cells treated with an inhibitor of glutathione (GSH) synthesis exhibited faster migration than LAT from untreated T cells under nonreducing conditions in gel electrophoresis. This suggested that LAT might form intramolecular disulfide bonds under conditions of chronic oxidative stress. Mutational analysis of Cys residues on LAT revealed that C117S or C26/29S mutants were partially insensitive to chronic oxidative stress (presumably because they could not become oxidized and form disulfide bridges), as shown by their continued presence in lipid rafts and by the ability of cells expressing these mutants to stimulate gene expression from interleukin-2 promoter-driven reporter genes. Oxidative stress also greatly reduced the TCR- and LAT-dependent activation of the transcription factors AP-1, NFAT, and NF-κB. However, expression of oxidation-insensitive LAT mutants in T cells partially reversed this inhibition. The authors suggest that the transmembrane helix of LAT might be sufficiently disrupted by chronic oxidative conditions such that LAT cannot remain localized to the lipid rafts. Other data suggested that disulfide bonds might form between Cys117 and probably Cys29. The data suggest that T cell hyporesponsiveness in chronic oxidative conditions results, in part, from improper localization of wild-type LAT, and thus ineffective signaling. For an excellent review on the function of the LAT protein, see the review by Wange . S. I. Gringhuis, E. A. M. Papendrecht-van der Voort, A. Leow, E. W. N. Levarht, F. C. Breedveld, C. L. Verweij, Effect of redox balance alterations on cellular localization of LAT and downstream T-cell receptor signaling pathways. Mol. Cell. Biol. 22 , 400-411 (2002). [Abstract] [Full Text] R. L. Wange, LAT, the linker for activation of T cells: A bridge between T cell-specific and general signaling pathways. Science's STKE (2000), http://www.stke.org/cgi/content/full/OC_sigtrans;2000/63/re1. [Abstract] [Full Text]