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

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 wer...

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Detalles Bibliográficos
Autores: Otano, I. (Itziar)|||/items/d3cfe573-3aef-4c87-aa71-d45016c59b03, Álvarez, M. (Maite)|||/items/869c2b2f-e806-47ac-8d76-303de908d205, Minute, L. (Luna)|||/items/7f5fd489-9a54-44f1-a8d0-167c80629de0, Ochoa-Nieto, M.C. (María del Carmen)|||/items/a26293bb-e79a-42a3-be52-dbf5208f3f89, Miguéliz-Basterra, I. (Itziar)|||/items/f8b05fe5-028a-4ebf-a3d8-bff420f4b61d, Molina, C. (Carmeen)|||/items/ab58ebab-8343-4857-9c58-b735ac06a44d, Azpilikueta, A. (Arantza)|||/items/8cb8f9c3-bb52-41cc-a19d-03de632308e9, Andrea, C.E. (Carlos Eduardo) de|||/items/e487698b-8d56-4c3e-8cba-40e33c78083a, Etxeberria, I. (Iñaki)|||/items/73830f45-c05b-49ed-a21a-f7cbacfc8f07, Fernández-de-Sanmamed-Gutiérrez, M. (Miguel)|||/items/35ac602c-f0ff-4664-bbd2-506afc96db09, Teijeira-Sánchez, A. (Álvaro)|||/items/8a954ec4-8458-46ea-b8e6-3165119bef30, Berraondo-López, P. (Pedro)|||/items/b1f8ccc3-8e08-4ece-967c-64ccfc0e5b91, Melero, I. (Ignacio)|||/items/82113ea8-7ce1-49d5-9ee3-42cf20db1c4e
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/66332
Acceso en línea:https://hdl.handle.net/10171/66332
Access Level:acceso abierto
Palabra clave:TNF
AICD
Mitochondria hyperpolarization
DNA damage
Descripción
Sumario: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 clinicalgrade 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.

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