Type I interferons directly regulate lymphocyte recirculation and cause transient blood lymphopenia.
Early viral infection is often associated with lymphopenia, a transient reduction of blood lymphocyte counts long before the onset of clinical symptoms. We have investigated lymphopenia in mice infected with vesicular stomatitis virus (VSV) or treated with the Toll-like receptor (TLR) agonists poly(I:C) and R-848. In all cases analyzed, lymphopenia was critically dependent on type I interferon receptor (IFNAR) signaling. With the use of bone marrow-chimeric mice, radioresistant cells, such as stroma and endothelium, could be excluded as type I interferon (IFN-alpha/beta) targets for the induction of lymphopenia. Instead, adoptive transfer experiments and studies in conditionally gene-targeted mice with a B- or T-cell-specific IFNAR deletion demonstrated that IFN-alpha/beta exerted a direct effect on lymphocytes that was necessary and largely sufficient to induce lymphopenia. Furthermore, after treatment with R-848, we found that other cytokines such as TNF-alpha also played a role in T-cell lymphopenia. Investigation of the molecular mechanism revealed that lymphopenia was mainly independent of G protein-coupled receptors (GPCRs) and chemokines. In an adhesion assay, B cells of poly(I:C)-treated mice showed moderately increased adhesion to ICAM-1 but not to VCAM-1. In conclusion, our data identify a new effect of direct IFN-alpha/beta stimulation of lymphocytes that profoundly affects lymphocyte redistribution.
Kamphuis
Elisabeth
E
Division of Immunology, Paul-Ehrlich-Institut, Paul-Ehrlich-Str 51-59, D-63225 Langen, Germany.
Junt
Tobias
T
Waibler
Zoe
Z
Forster
Reinhold
R
Kalinke
Ulrich
U
D000818:Animals; D001773:Blood Cells; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016207:Cytokines / Q000502:physiology; D007370:Interferon Type I / Q000502:physiology*; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology*; D008231:Lymphopenia / Q000209:etiology*; D051379:Mice; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D051193:Toll-Like Receptors / Q000819:agonists; D014721:Vesicular stomatitis Indiana virus
D015815:Cell Adhesion Molecules; D016207:Cytokines; D007370:Interferon Type I; D051193:Toll-Like Receptors; D053633:Receptor, Interferon alpha-beta