Abstract
T cells are used in many cell-based cancer treatments. However, oxidative stress that is induced during various chronic inflammatory conditions, such as cancer, can impair the immune system and have detrimental effects on T cell function. In this study, we have investigated the sensitivity of different human T cell subsets to H(2)O(2)-induced oxidative stress. We showed that central memory (CD45RA(-)CCR7(+)) and effector memory (CD45RA(-)CCR7(-)) T cells are more sensitive to H(2)O(2) as compared with naive (CD45RA(+)CCR7(+)) T cells. Furthermore, the study showed that CD8(+) effector memory T cells are more sensitive to low levels of H(2)O(2) (5 microM) compared with other types of T cells investigated. H(2)O(2)-exposed CD45RO(+) T cells showed mitochondrial depolarization prior to caspase 3 activity. Moreover, the pan-caspase inhibitor z-Val-Ala-Asp(OMe)-fluoromethylketone rescued cells from death. These experiments suggest that H(2)O(2)-induced cell death of CD45RO(+) T cells acts via the mitochondrial pathway and that caspase involvement is needed. This study suggests that oxidative stress in cancer patients can be disadvantageous for T cell-based adoptive cell transfer therapies, since effector memory T cells are the primary phenotype of the cells administered.
Highlights
Why The JI? Submit online. Rapid Reviews! 30 days* from submission to initial decision No Triage! Every submission reviewed by practicing scientists Fast Publication! 4 weeks from acceptance to publicatio
This observation was confirmed by a corresponding increase in the percentage of CD45RAϩ T cells as tested using an anti-CD45RA mAb (Fig. 1B). We investigated whether this H2O2-induced shift in T cell subsets, leading to a decreased proportion of CD45ROϩ T cells in the viable cell population, was a result of differential proliferation or a consequence of enhanced cell death of this particular subset
We conclude that the decrease in the percentage of CD45ROϩ T cells is due to the enhanced sensitivity of this subset to H2O2-induced cell death
Summary
ROS, reactive oxygen species; TEM, effector memory T cells; TCM, central memory T cells; 7-AAD, 7-aminoactinomycin D; z-VADFMK, z-Val-Ala-Asp(OMe)-fluoromethylketone; TMRE, tetramethylrhodamine ethyl ester; FLICA, fluorochrome inhibitor of caspases; FSC, forward scatter; SSC, side scatter. The negative effect of NO and H2O2 produced from activated macrophages and granulocytes on T and NK cell functions is well established. Monocytes can inhibit in vitro human NK cell-mediated cytotoxicity via secretion of H2O2, leading to induction of cell death [19]. Macrophage-derived NO markedly reduces the phosphorylation and activation of JAK3/STAT5 signal transduction proteins, inhibiting the proliferative responses of T cells to IL-2 [20]. Activated granulocytes and oxidative stress mediated by H2O2 in the circulation of patients with advanced cancer was recently described [14]. H2O2 secretion by activated macrophages and granulocytes has been suggested as one possible mechanism behind the tumor-induced immune suppression with decreased signal transduction and poor effector functions of T cells and NK cells observed in cancer patients. Mitochondrial membrane potential and caspase 3 activity were analyzed, suggested that the mitochondrial pathway is the primary cell death pathway for CD45ROϩ T cells exposed to low levels of H2O2
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
