Inhibition of activated/memory (CD45RO(+)) T cells by oxidative stress associated with block of NF-kappa B activation

Impaired immune responses in cancer patients have been associated with oxid ative stress. Increased levels of reactive oxygen species released from act ivated, tumor-infiltrating macrophages or granulocytes may therefore consti tute a hurdle for effective immunotherapy against cancer. In this study, we investigated functional consequences and molecular events in T cells expos ed to low levels of oxidative stress. We observed that cytokine production of human PBMC, upon stimulation with an HLA-A*0201-restricted influenza pep tide and nonspecific receptor cross-linking, was reduced after exposure to micromolar levels of H2O2. Functional impairment as measured by IFN-gamma r elease occurred earlier and at lower doses of exogenously added H2O2 than r equired to induce apoptosis. This suggests that there is a dose window of o xidative stress leading to T cell unresponsiveness in the absence of apopto sis. The reduction of Th1 cytokines, induced by H2O2, was predominantly obs erved in memory/effector (CD45RO(+)) T cells and correlated with a block in NF-kappaB activation. IL-10 production was more profoundly influenced by l ow doses of H2O2 than IFN-gamma, TNF-alpha, and IL-2. The influence of H2O2 on production of IL-10 was not significantly different between memory/acti vated and naive T cells. These observations suggest that Th1 and Th2 cytoki nes are differently regulated under conditions of oxidative stress. Taken t ogether, these findings may explain why Ag-experienced, CD45RO(+), T cells found in the tumor milieu are functionally suppressed.