Human CD8 T cells are susceptible to TNF-mediated activation-induced cell death
Otano I (1,2), Alvarez M (1,2), Minute L (1,2), Ochoa MC (1,2,3,4), Migueliz I (2,4), Molina C (1,2), Azpilikueta A (1,2), de Andrea CE (2,3,5,6), Etxeberria I (1,2), Sanmamed MF (1,2,7), Teijeira Á (1,2,3), Berraondo P (1,2,3), Melero I (1,2,3,7,4).
(1) Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain.
(2) Navarra Institute for Health Research (IDISNA), Pamplona, Spain.
(3) Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
(4) Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, Pamplona, Spain.
(5) Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain.
(6) Department of Histology and Pathology, Universidad de Navarra, Pamplona, Spain.
(7) Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain.
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.
Methods: 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.
Results: 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.
Conclusion: 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.
CITA DEL ARTÍCULO Theranostics. 2020 Mar 15;10(10):4481-4489. doi: 10.7150/thno.41646. eCollection 2020