Oxidative‐stress‐induced T lymphocyte hyporesponsiveness is caused by structural modification rather than proteasomal degradation of crucial TCR signaling molecules

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Abstract
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‐ζ, p56lck and LAT) but not all (e.g. TCR‐αβ and CD3‐ϵ) 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‐ζ and the membrane‐proximal domain of p56lck as potential targets for modifications induced by reactive oxygen species. Oxidative‐stress‐exposed proteins were differentially susceptible to proteasomal degradation: whereas modified TCR‐ζ was relatively resistant, reactive oxygen species (ROS)‐altered LAT and p56lck 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‐ζ signals combined with unaltered TCR‐αβ and CD3‐ϵexpression levels: the TCR‐ζ chain in hyporesponsive T cells is still expressed but no longer detectable by certain mAb recognizing ROS‐sensitive epitopes.

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