Sepsis Impairs IFN-? Production in CD8 T Cells through Changes in Local Chromatin Landscape
Por:
Cisneros-Segura J.A., Rodríguez-Rodríguez N., Albarrán-Godínez A., García-González H.B., Rodríguez-Osorio C.A., Valdés-Ferrer S.I., Tapia-Urzúa G., Recillas-Targa F., Madera-Salcedo I.K., Rosetti F., Crispín J.C.
Publicada:
1 ene 2024
Resumen:
Sepsis is a complex condition of inflammatory and immune dysregulation, triggered by severe infection. In survivors, chronic inflammation and immune dysregulation linger, facilitating the emergence of infections. CD8 dysfunction contributes to immunosuppression in sepsis survivors. We devised an animal model that enabled us to identify and analyze CD8-intrinsic defects induced by sepsis. We adoptively transferred CD45.1 CD8 OT-I T cells into CD45.2 congenic mice and subjected them to cecal ligature and puncture, to induce abdominal sepsis. One month later, we isolated the transferred CD8 cells. Surface marker expression confirmed they had not been activated through the TCR. CD8 OT-I T cells isolated from septic (or sham-operated) mice were transferred to second recipients, which were challenged with OVA-expressing Listeria monocytogenes. We compared effector capacities between OT-I cells exposed to sepsis and control cells. Naive mice that received OT-I cells exposed to sepsis had higher bacterial burden and a shorter survival when challenged with OVA-expressing L. monocytogenes. OT-I cells isolated from septic mice produced less IFN-? but had conserved activation, expansion potential, and cytotoxic function. We observed lower transcript levels of IFN-? and of the long noncoding RNA Ifng-as1, a local regulator of the epigenetic landscape, in cells exposed to sepsis. Accordingly, local abundance of a histone modification characteristic of active promoter regions was reduced in sepsis-exposed CD8 T cells. Our results identify a mechanism through which inflammation in the context of sepsis affects CD8 T cell function intrinsically. Copyright © 2024 by The American Association of Immunologists, Inc.
Filiaciones:
Cisneros-Segura J.A.:
Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
Programa de Maestría y Doctorado en Ciencias Bioquímicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
Rodríguez-Rodríguez N.:
Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
Medical Research Council, Laboratory of Molecular Biology, Cambridge, United Kingdom
Albarrán-Godínez A.:
Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
García-González H.B.:
Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
Rodríguez-Osorio C.A.:
Departament of Critical Care, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
Respiratory Intensive Care Unit, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas”, Mexico City, Mexico
Valdés-Ferrer S.I.:
Department of Neurology & Psychiatry, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
Center for Biomedical Science, Feinstein Institutes for Medical Research, New York, NY, United States
Tapia-Urzúa G.:
Instituto de Fisiología Celular, Departamento de Genética Molecular, Universidad Nacional Autónoma de México, Mexico City, Mexico
Recillas-Targa F.:
Instituto de Fisiología Celular, Departamento de Genética Molecular, Universidad Nacional Autónoma de México, Mexico City, Mexico
Madera-Salcedo I.K.:
Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
Rosetti F.:
Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
Crispín J.C.:
Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
Escuela de Medicina y Ciencias de la Salud, Tecnologico de Monterrey, Mexico City, Mexico
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