1. Induction of thymic atrophy and loss of thymic output by type-I interferons during chronic viral infection.
- Author
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Démoulins T, Baron ML, Gauchat D, Kettaf N, Reed SJ, Charpentier T, Kalinke U, Lamarre A, Ahmed R, Sékaly RP, Sarkar S, and Kalia V
- Subjects
- Animals, Atrophy genetics, Atrophy immunology, Atrophy pathology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes virology, Chronic Disease, Female, Gene Expression Regulation, Humans, Immunologic Memory, Interferon-alpha genetics, Interferon-beta genetics, Lymph Nodes immunology, Lymph Nodes pathology, Lymph Nodes virology, Lymphocyte Depletion, Lymphocytic Choriomeningitis genetics, Lymphocytic Choriomeningitis immunology, Lymphocytic Choriomeningitis pathology, Lymphocytic choriomeningitis virus pathogenicity, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptor, Interferon alpha-beta deficiency, Receptor, Interferon alpha-beta genetics, Receptor, Interferon alpha-beta immunology, Signal Transduction immunology, Single-Cell Analysis, Thymocytes immunology, Thymocytes pathology, Thymus Gland immunology, Thymus Gland pathology, Atrophy virology, Interferon-alpha immunology, Interferon-beta immunology, Lymphocytic Choriomeningitis virology, Lymphocytic choriomeningitis virus immunology, Thymocytes virology, Thymus Gland virology
- Abstract
Type-I interferon (IFN-I) signals exert a critical role in disease progression during viral infections. However, the immunomodulatory mechanisms by which IFN-I dictates disease outcomes remain to be fully defined. Here we report that IFN-I signals mediate thymic atrophy in viral infections, with more severe and prolonged loss of thymic output and unique kinetics and subtypes of IFN-α/β expression in chronic infection compared to acute infection. Loss of thymic output was linked to inhibition of early stages of thymopoiesis (DN1-DN2 transition, and DN3 proliferation) and pronounced apoptosis during the late DP stage. Notably, infection-associated thymic defects were largely abrogated upon ablation of IFNαβR and partially mitigated in the absence of CD8 T cells, thus implicating direct as well as indirect effects of IFN-I on thymocytes. These findings provide mechanistic underpinnings for immunotherapeutic strategies targeting IFN-1 signals to manipulate disease outcomes during chronic infections and cancers., (Copyright © 2021. Published by Elsevier Inc.)
- Published
- 2022
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