Preferential Cell Death of CD8+ Effector Memory (CCR7-CD45RA-) T Cells by Hydrogen Peroxide-Induced Oxidative Stress

• Published in: The Journal of immunology (1950) Vol. 174; no. 10; pp. 6080 - 6087
• Main Authors: Takahashi, Akihiro, Hanson, Mikael G. V, Norell, Hakan R, Havelka, Aleksandra Mandic, Kono, Koji, Malmberg, Karl-Johan, Kiessling, Rolf V. R
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15-05-2005
• Subjects: Amino Acid Chloromethyl Ketones - pharmacology; Caspase Inhibitors; Cell Death - drug effects; Cell Death - immunology; Cells, Cultured; Cytotoxicity, Immunologic - drug effects; Dose-Response Relationship, Immunologic; Growth Inhibitors - pharmacology; Humans; Hydrogen Peroxide - pharmacology; Immunologic Memory - drug effects; Intracellular Membranes - drug effects; Leukocyte Common Antigens - biosynthesis; Medicin och hälsovetenskap; Membrane Potentials - drug effects; Membrane Potentials - immunology; Mitochondria - drug effects; Mitochondria - immunology; Oxidative Stress - drug effects; Oxidative Stress - immunology; Permeability - drug effects; Receptors, CCR7; Receptors, Chemokine - biosynthesis; T-Lymphocytes, Cytotoxic - cytology; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism
• DOI: 10.4049/jimmunol.174.10.6080
• EISSN: 1550-6606
• ISSN: 0022-1767

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.