Human CD8 T cells are susceptible to TNF-mediated activation-induced cell death

• Published in: Theranostics 2020-01, Vol.10 (10), p.4481-4489
• Main Authors: Otano, Itziar, Alvarez, Maite, Minute, Luna, Ochoa, María Carmen, Migueliz, Itziar, Molina, Carmen, Azpilikueta, Arantza, de Andrea, Carlos E, Etxeberria, Iñaki, Sanmamed, Miguel F, Teijeira, Álvaro, Berraondo, Pedro, Melero, Ignacio
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Antibodies; Antigens; Apoptosis; Apoptosis - drug effects; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - drug effects; Cell death; DNA damage; Etanercept - pharmacology; Female; Flow cytometry; Healthy Volunteers; Humans; Immunotherapy; Infliximab - pharmacology; Leukocytes, Mononuclear - cytology; Lymphocyte Activation - drug effects; Lymphocyte receptors; Lymphocytes; Lymphocytes, Tumor-Infiltrating - cytology; Lymphocytes, Tumor-Infiltrating - drug effects; Male; Middle Aged; Mitochondria - drug effects; Neoplasms - drug therapy; Neoplasms - immunology; Oxidative stress; Oxidative Stress - drug effects; Peptides; Research Paper; T cell receptors; Tumor Necrosis Factor Inhibitors - pharmacology; Viral infections
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.41646

Activation-induced cell death (AICD) is a complex immunoregulatory mechanism that causes the demise of a fraction of T-lymphocytes upon antigen-driven activation. In the present study we investigated the direct role of TNF in AICD of CD8 T lymphocytes. : Human peripheral mononuclear cells were isolated from healthy donors and fresh tumor-infiltrating lymphocytes were obtained from cancer patients undergoing surgery. T cells were activated with anti-CD3/CD28 mAbs or with a pool of virus peptides, in combination with clinical-grade TNF blocking agents. : A portion of CD8 T cells undergoes apoptosis upon CD3/CD28 activation in a manner that is partially prevented by the clinically used anti-TNF agents infliximab and etanercept. TNF-mediated AICD was also observed upon activation of virus-specific CD8 T cells and tumor-infiltrating CD8 T lymphocytes. The mechanism of TNF-driven T cell death involves TNFR2 and production of mitochondrial oxygen free radicals which damage DNA. : The use of TNF blocking agents reduces oxidative stress, hyperpolarization of mitochondria, and the generation of DNA damage in CD8 T celss undergoing activation. The fact that TNF mediates AICD in human tumor-reactive CD8 T cells suggests that the use of TNF-blocking agents can be exploited in immunotherapy strategies.