O01

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.