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.
Keywords:
Acute; CD8 T cells; Chronic; Thymic atrophy; Thymopoiesis; Type-I interferons; Viral infection.
Copyright © 2021. Published by Elsevier Inc.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Atrophy / genetics
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Atrophy / immunology
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Atrophy / pathology
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Atrophy / virology*
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / virology
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Chronic Disease
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Female
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Gene Expression Regulation
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Humans
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Immunologic Memory
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Interferon-alpha / genetics
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Interferon-alpha / immunology*
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Interferon-beta / genetics
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Interferon-beta / immunology*
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Lymph Nodes / immunology
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Lymph Nodes / pathology
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Lymph Nodes / virology
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Lymphocyte Depletion
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Lymphocytic Choriomeningitis / genetics
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Lymphocytic Choriomeningitis / immunology
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Lymphocytic Choriomeningitis / pathology
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Lymphocytic Choriomeningitis / virology*
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Lymphocytic choriomeningitis virus / immunology*
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Lymphocytic choriomeningitis virus / pathogenicity
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Receptor, Interferon alpha-beta / deficiency
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Receptor, Interferon alpha-beta / genetics
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Receptor, Interferon alpha-beta / immunology
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Signal Transduction / immunology
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Single-Cell Analysis
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Thymocytes / immunology
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Thymocytes / pathology
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Thymocytes / virology*
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Thymus Gland / immunology
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Thymus Gland / pathology
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Thymus Gland / virology*
Substances
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Interferon-alpha
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Receptor, Interferon alpha-beta
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Interferon-beta