Induction of thymic atrophy and loss of thymic output by type-I interferons during chronic viral infection

Virology. 2022 Feb:567:77-86. doi: 10.1016/j.virol.2021.12.007. Epub 2021 Dec 24.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atrophy / genetics
  • Atrophy / immunology
  • Atrophy / pathology
  • Atrophy / virology*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / virology
  • Chronic Disease
  • Female
  • Gene Expression Regulation
  • Humans
  • Immunologic Memory
  • Interferon-alpha / genetics
  • Interferon-alpha / immunology*
  • Interferon-beta / genetics
  • Interferon-beta / immunology*
  • Lymph Nodes / immunology
  • Lymph Nodes / pathology
  • Lymph Nodes / virology
  • Lymphocyte Depletion
  • Lymphocytic Choriomeningitis / genetics
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic Choriomeningitis / pathology
  • Lymphocytic Choriomeningitis / virology*
  • Lymphocytic choriomeningitis virus / immunology*
  • 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
  • Thymocytes / virology*
  • Thymus Gland / immunology
  • Thymus Gland / pathology
  • Thymus Gland / virology*

Substances

  • Interferon-alpha
  • Receptor, Interferon alpha-beta
  • Interferon-beta