Oxidative-stress-induced T lymphocyte hyporesponsiveness is caused by structural modification rather than proteasomal degradation of crucial TCR signaling molecules.
In several human pathologies (e.g. cancer, rheumatoid arthritis, AIDS and leprosy) oxidative stress induces T cell hyporesponsiveness. Hyporesponsive T cells often appear to display impaired expression of some (e.g. TCR-zeta, p56(lck) and LAT) but not all (e.g. TCR-alphabeta and CD3-epsilon) crucial TCR-proximal signaling molecules but the underlying mechanisms have as yet not been identified. Using an in vitro system for oxidative-stress-induced T cell hyporesponsiveness we here report two sequential effects of oxidative stress on TCR signaling molecules: protein alterations and proteasomal degradation. We have identified the C-terminal part of TCR-zeta and the membrane-proximal domain of p56(lck) as potential targets for modifications induced by reactive oxygen species. Oxidative-stress-exposed proteins were differentially susceptible to proteasomal degradation: whereas modified TCR-zeta was relatively resistant, reactive oxygen species (ROS)-altered LAT and p56(lck) were much more susceptible. Importantly, we found that T cell hyporesponsiveness best correlated with ROS-dependent protein alteration since inhibition of proteasomal degradation did not restore function. Finally, our data provide an explanation for the paradox of reduced TCR-zeta signals combined with unaltered TCR-alphabeta and CD3-epsilon expression levels: the TCR-zeta chain in hyporesponsive T cells is still expressed but no longer detectable by certain mAb recognizing ROS-sensitive epitopes.
Cemerski
Saso
S
Tolerance and Autoimmunity section, INSERM U563, Toulouse, France.
van Meerwijk
Joost P M
JP
Romagnoli
Paola
P
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000378:metabolism; D018920:Coculture Techniques; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D008565:Membrane Proteins; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000378:metabolism*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C110810:LAT protein, human; D008565:Membrane Proteins; D009097:Multienzyme Complexes; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D016692:Receptors, Antigen, T-Cell, gamma-delta; C067713:lactacystin; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine