Type I interferons directly regulate lymphocyte recirculation and cause transient blood lymphopenia

Area of Science:

• Immunology
• Virology
• Cell Biology

Background:

• Early viral infections often lead to lymphopenia, a decrease in blood lymphocyte counts preceding clinical symptoms.
• The precise mechanisms driving virus-induced lymphopenia remain incompletely understood.

Purpose of the Study:

• To investigate the mechanisms underlying lymphopenia induced by viral infection and Toll-like receptor (TLR) agonists.
• To determine the specific cell types and signaling pathways involved in interferon-mediated lymphopenia.

Main Methods:

• Infection of mice with vesicular stomatitis virus (VSV) or treatment with TLR agonists (poly(I:C), R-848).
• Utilized bone marrow-chimeric mice and conditionally gene-targeted mice (B-cell or T-cell specific IFNAR deletion).
• Adoptive transfer experiments, cytokine analysis (TNF-alpha), and cell adhesion assays (ICAM-1, VCAM-1).

Main Results:

• Lymphopenia was critically dependent on type I interferon receptor (IFNAR) signaling in all models.
• Type I interferons (IFN-alpha/beta) directly affect lymphocytes, inducing lymphopenia, excluding radioresistant cells like stroma and endothelium.
• TNF-alpha also contributed to T-cell lymphopenia after R-848 treatment.
• Lymphopenia mechanisms were largely independent of G protein-coupled receptors (GPCRs) and chemokines.

Conclusions:

• Type I interferons directly stimulate lymphocytes, causing lymphopenia and affecting lymphocyte redistribution.
• This identifies a novel mechanism of interferon action on lymphocytes during viral infections and immune stimulation.