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

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-´, p56 lck and LAT) but not all (e.g. TCR- § g and CD3-4 ) 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-´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-´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-´signals combined with unaltered TCR- § g and CD3-4 expression levels: the TCR-´chain in hyporesponsive T cells is still expressed but no longer detectable by certain mAb recognizing ROS-sensitive epitopes.

Tumor-Associated CD8+ T Cell Tolerance Induced by Bone Marrow-Derived Immature Myeloid Cells

“…One of the possible mechanisms of this effect could be that ImC from tumor-bearing mice have higher arginase I activity and produce substantially higher level of reactive oxygen species (ROS) than their control counterparts (32). Important role of ROS in T cell defects has been demonstrated previously (33,34). Several studies demonstrated an important role of arginase I in immune suppression by myeloid cells, which is mediated by depletion of L-arginine (35)(36)(37).…”

Age-Associated Decline in Effective Immune Synapse Formation of CD4+ T Cells Is Reversed by Vitamin E Supplementation

“…In fact, microdomains composed primarily of cholesterol and sphingolipids, commonly known as lipid rafts, are found throughout the plasma membrane and have been shown to be essential for effective immune synapse formation (55). Oxidative stress can prevent lipid raft-associated proteins from entering the microdomains (56), and can prevent the structural modifications required for the entry of these proteins into lipid microdomains (57). Thus, vitamin E could improve immune synapse formation by affecting the association of signaling proteins within these microdomains.…”

Redox regulation of the proteasome in T lymphocytes during aging

“…Oxidative stress has often been implicated in the functional loss accompanying aging, more specifically the involvement of thiols in T cell responsiveness to external stimuli [25][26][27][28][29]. However, there is little evidence for the effect of oxidative stress on proteasomal activities in primary human T lymphocytes.…”