XCR1 expression licenses anti-viral effector functions of human conventional dendritic cells type 1
HEGER L. 1, HATSCHER L. 2, LEHMANN C. 1, AMON L. 1, KASZUBOWSKI T. 1, LÜHR J. 3, SCHAFT N. 4, DÖRRIE J. 4, IRRGANG P. 5, TENBUSCH M. 5, LIANG C. 6, KUNZ M. 6, SOCHER E. 7, AUTENRIETH S. 8, PURBOJO A. 9, SIRBU H. 10, HARTMANN A. 11, ALEXIOU C. 12, CESNJEVAR R. 9,13, DUDZIAK D. 1,14
1 Department of Dermatology, Laboratory of DC Biology, Uniklinikum Erlangen, Erlangen, Germany; 2 Uniklinikum Erlangen, Erlangen, Germany; 3 Nano-Optics, Max Planck Institute for the Science of Light, Erlangen, Germany; 4 Department of Dermatology, RNA-based immunotherapy, Uniklinikum Erlangen, Erlangen, Germany; 5 Institute of Clinical and Moelcular Virology, Uniklinikum Erlangen, Erlangen, Germany; 6 Chair of Medical Informatics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; 7 Functional and Clinical Anatomy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; 8 Research Group "Dendritic Cells in Infection and Cancer" (F171), German Cancer Research Center (DKFZ), Heidelberg, Germany; 9 Department of Pediatric Cardiac Surgery, Uniklinikum Erlangen, Erlangen, Germany; 10 Department of Thoracic Surgery, Uniklinikum Erlangen, Erlangen, Germany; 11 Department of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; 12 Department of Otorhinolaryngoly, Section of Experimental Oncology and Nanomedicine, Uniklinikum Erlangen, Erlangen, Germany; 13 Department of Pediatric Cardiac Surgery, University Zurich, Zurich, Switzerland; 14 Institute of Immunology, Friedrich-Schiller University of Jena, University Hospital Jena, Jena, Germany
Introduction: Dendritic cells (DCs) are major regulators of innate and adaptive immune responses. DCs can be classified into plasmacytoid DCs and conventional DCs (cDCs) type 1 and 2. Murine and human cDC1 share the mRNA expression of XCR1. Murine studies indicated a specific role of the XCR1-XCL1 axis in the induction of immune responses. We observed that human cDC1 can be distinguished into XCR1- and XCR1+ cDC1.
Objective: As human cDC2 consist of two functional distinct subpopulations (DC2 and DC3), we were interested whether XCR1- and XCR1+ cDC1 represent functionally distinct subsets.
Methods: For functional/phenotypical characterization, we isolated human XCR1+ and XCR1- cDC1 by FACS-based cell sorting from blood, spleen, tonsils, thymus, and lungs, performed transcriptional analysis by Nanostring technology, and tested functional capacity of the cells (TLR-stimulation, T cell and NK cell co-cultures, infection assays, DC differentiation assays).
Results: We found that XCR1+ cDC1 were more mature on transcriptional level compared to XCR1- cDC1. After TLR stimulation, XCR1+ cDC1 excelled in the secretion of inflammatory cytokines. While XCR1+ and XCR1- cDC1 induced comparable T cell responses, XCR1+ cDC1 were superior in the activation of NK cells due to enhanced secretion of IL-12. Further, XCR1+ cDC1 more efficiently induced an anti-viral state in epithelial cells leading to reduced infection by influenza virus type A. Moreover, we identified that culture of XCR1- cDC1 under DC differentiation conditions induced XCR1 expression. Subsequently, these new XCR1+ cDC1 were able to secrete comparable amounts of inflammatory cytokines to originally XCR1+ cDC1.
Conclusions: Our data indicate that only XCR1+ cDC1 possess the full functional capacity of cDC1. As XCR1- cDC1 are able to acquire XCR1 expression under DC differentiation conditions, they seem to represent an intermediate precursor type between pre-cDC1 and terminal differentiated cDC1 that is present in blood, lymphoid as well as non-lymphoid tissues.