Immune Cell Profiling of IFN-λ Response Shows pDCs Express Highest Level of IFN-λR1 and Are Directly Responsive via the JAK-STAT Pathway.
The interferon lambda (IFN-λ) cytokines have well-known antiviral properties, yet their contribution to immune regulation is not well understood. Epithelial cells represent the major target cell of IFN-λ; peripheral blood mononuclear cells are generally considered nonresponsive, with the exception of plasmacytoid dendritic cells (pDCs). In this study we aimed to define the potential for discrete subpopulations of cells to directly respond to IFN-λ. Analysis of peripheral blood leukocytes reveals that, while pDCs uniformly express the highest levels of IFN-λ receptor, a small proportion of B cells and monocytes also express the receptor. Nevertheless, B cells and monocytes respond poorly to IFN-λ stimulation in vitro, with minimal STAT phosphorylation and interferon-stimulated gene (ISG) induction observed. We confirm that pDCs respond to IFN-λ in vitro, upregulating their expression of pSTAT1, pSTAT3, and pSTAT5. However, we found that pDCs do not upregulate pSTAT6 in response to IFN-λ treatment. Our results highlight unique aspects of the response to IFN-λ and confirm that while the IFN-λ receptor is expressed by a small proportion of several different circulating immune cell lineages, under normal conditions only pDCs respond to IFN-λ stimulation with robust STAT phosphorylation and ISG induction. The difference in STAT6 responsiveness of pDCs to type I and type III interferons may help explain the divergence in their biological activities.
1 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin , Dublin, Ireland .
Aoife
A
Kelly
1 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin , Dublin, Ireland .
Mark W
MW
Robinson
1 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin , Dublin, Ireland .
Gerard
G
Roche
2 Department of Molecular Microbiology and Immunology, Brown University , Providence, Rhode Island.
Christine A
CA
Biron
1 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin , Dublin, Ireland .|3 School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin , Dublin, Ireland .
Cliona
C
O'Farrelly
4 Centre for Colorectal Disease, Education and Research Centre, St. Vincent's University Hospital , Dublin, Ireland .|5 School of Medicine and Medical Sciences, University College Dublin , Dublin, Ireland .
Elizabeth J
EJ
Ryan
D015703:Antigens, CD / Q000378:metabolism; D000998:Antiviral Agents / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016130:Immunophenotyping; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology; D007372:Interferons / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D017471:Receptors, Interferon / Q000235:genetics* / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D007378:Interleukins; D000095022:Interferon Lambda
D015703:Antigens, CD; D000998:Antiviral Agents; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha; D007372:Interferons; D053612:Janus Kinases; D017471:Receptors, Interferon; D050791:STAT Transcription Factors; C000624353:interferon-lambda, human; D007378:Interleukins; D000095022:Interferon Lambda
JAK-STAT; Type III IFNs; dendritic cells; peripheral blood mononuclear cells