background_1 background_2

Meeting report : DC2018

Meeting report from Marion Humbert, recipient of a CFCD travel award.

The 15th International Symposium on Dendritic Cells, DC2018, took place this year in Aachen, Germany. It was an intense program with a great number of confirmed speakers, selected oral presentations and posters, which covered a very broad range of topics in the field of Dendritic Cells, from ontogeny and development to DC vaccination and immunotherapy.
Here, I attempt to summarize the presentations that particularly caught my attention.

Boris Reizis (New York University School of medicine, US) gave a presentation on the generation of functional cross-presenting cDC1 and the role of Notch signaling in this mechanism. Notch signaling was already known to be important for cDC1 differentiation in vivo. Briefly, his team showed that adding OP9-DL1 (OP9 cells expressing the Notch ligand DL1) in culture of murine or human bone marrow-derived cells, in addition to FLT3L greatly enhanced the yield of cDC1 cells, compared with FLT3L alone. This is of importance for future research purposes on cDC1 and also for therapeutic applications.
Florent Ginhoux (Singapore Immunology Network, Singapore) presented data about the classification of DC from an ontogeny point of view. The use of single-cell RNAseq and CyTOF allowed his team to unravel the human DC lineage, where the common DC progenitors (CDP) give rise to pre-DC and plasmacytoid DC (pDC) in the bone marrow, pre-DC subsequently giving rise to cDC1 and cDC2. Pre-DC and pDC are in close phenotypical proximity, as they share some markers previously thought to be pDC-restricted. Functional assays revealed IFN-I production by pDC and induction of T cell activation by pre-DC. He also showed unpublished results in mouse where pDC and DC potential from progenitors were compared. They found pre-pDC-primed cells (early committed to pDC) in the common lymphoid DC progenitors (CLP) population. Florent Ginhoux raised the question whether pDC would be more related to innate lymphoid cells than DC and proposed new potential names for this cell population.

David Jackson (University of Oxford, UK) presented results about the mechanisms of DC trafficking from tissue to lymph nodes via the lymphatics. The model he proposed was that 1) DC enters lymphatics thanks to a chemokine gradient (including CCL21 and CX3CL1) and 2) they synthesize a surface hyaluronan glycocalyx that acts as adhesin. 3) The interaction of DC with lymphatic endothelial cells (LEC) is enabled by the formation of a hyaluronan-LYVE-1 (LYVE-1 is expressed by LEC) tetramer. 4) DCs can finally squeeze and intravasate.
Sebastian Amigorena (Institut Curie, Paris, France) presented results on the heterochromatin immune function in myeloid cells. His team found a role for gene expression silencing in DC, more particularly of the histone methyltransferase Suv39h1, with a loss of Suv39h1 leading to increased pro-inflammatory cytokine expression and increased levels of cytosolic DNA in bone marrow-derived DC after LPS stimulation. They observed a repression of transposable elements (TE) expression in DC by Suv39h1. The model they propose is that upon LPS stimulation, there are decreased levels of Suv39h1 in DC, leading to decreased levels of H3K9me3. This induces an enhanced expression of TE RNA with subsequent increased levels of cytosolic TE DNA. Cytosolic DNA is sensed by cGAS (cGAS ChIP-seq revealed enrichment in individual TE binding), leading to IFN-I and pro-inflammatory cytokine production via the cGAS-cGAMP-STING pathway.
Jose Villadangos (University of Melbourne, Australia) presented a new cell type with hybrid cDC1-B cell phenotype that he named ACDC, for ‘antibody-coated DC’. His team identified complement C3 as a new target of MARCH1, involved in the recycling of MHCII-peptide complexes from the surface, in addition to MHCII and CD86. MHCII is necessary and sufficient to cause C3 deposition at the cell surface. The formation of covalently linked C3-MHCII complexes regulates ACDC and cDC1 homeostasis. The function of ACDC and the mechanism of C3-MHCII complexes formation remain to be determined.

In the session ‘DC in allergy and autoimmunity’, Burkhard Becher (University of Zurich, Switzerland) gave a presentation about the impact of GM-CSF dysregulation on CNS inflammation. When there is an increased secretion of GM-CSF, myeloid cells expand, infiltrate the CNS and phagocytose myelin, leading to CNS inflammation and neurological deficits. He explained this phenomenon was not related to autoimmunity and used the term ‘cytokinopathies’ to describe chronic inflammatory diseases. He then showed unpublished data on the source of GM-CSF during neuroinflammation. Using different systems of fate-map reporters (FROG mice that allow the tracking of GM-CSF-producing cells, suicide FROG mice, in which GM-CSF-producing cells die, and cytokine-blind FROG mice) his team showed that encephalitogenic CD4+ T cells are the main source of GM-CSF in the CNS, with the sensing of IL-23 and IL-1 being crucial for the dysregulation of GM-CSF production in these cells.
Ursula Grohman (University of Perugia, Italy) presented data on an immunoregulatory pathway involving both arginine and tryptophan metabolism. IDO1 is known to be involved in the induction of Tregs. Her team showed that CD11c+ DC can express both Arg1 and IDO1, which render them immunosuppressive. TGF-β induces the co-expression of IDO1 and Arg1 in DC, with Arg1 expression being required for IDO1 induction.

Andreas Meyerhans (Pompeu Fabra University, Barcelona, Spain) showed results on the role of the XCL1-XCR1 axis in viral infection, in a selected presentation of the ‘DC in chronic infections’ session. Using weighted gene co-expression network analysis (WGCNA), his team analyzed the genes that were co-regulated in chronic and acute LCMV infection. They found that XCL1 was mainly produced by virus-specific CD8+ T cells during the shift from acute to chronic infection. The XCL1-XCR1 interaction on XCR1+ DC leads to antigen presentation to virus-specific CD8+ T cells, allowing control of viral loads during the chronic phase of infection. This suggests XCR1+ DCs-targeting vaccines against viral infections could be of potential therapeutic interest.
In a selected presentation in the session ‘DC in cancer and cancer immunotherapy’, Jan Böttcher (Technical University of Munich, Germany) presented results about the recruitment of cDC1, critical for anti-tumor immunity, into the tumor (worked performed in Caetano Reis e Sousa’s lab, Francis Crick institute, London, UK). Böttcher and colleagues observed an accumulation of NK cells in the tumor, with NK and cDC1 in close proximity. cDC1 recruitment was dependent on the production of chemokines (CCL5 and XCL1) by NK cells. The accumulation of cDC1 in the tumor was controlled by COX activity; COX-dependent PGE2 production regulated the local positioning of intratumoral cDC1, leading to immune control in COX-deficient tumors and immune escape in COX-sufficient tumors. In cancer patients, high expression of cDC1 and NK cells transcripts in tumor was associated with increased survival.

Wolfgang Kastenmüller (Institute of Experimental Immunology, Bonn, Germany) gave a keynote lecture on the CD8+ T cell priming dynamics after viral (MVA) infection. Briefly, primed CD8+ T cells secrete CCL3 and CCL4, leading to intranodal pDC migration towards CD8+ T cells priming sites, and XCL1, which recruit XCR1+ DC. This induces a reorganization of cell localization in the lymph nodes and cooperation between pDC and XCR1+ DC, with increased maturation and cross-presentation of XCR1+ DC thanks to IFN-I production by pDC, subsequently leading to an enhanced anti-viral CD8+ T cell response.
During his keynote lecture, Bart Lambrecht (Ghent University, Belgium) presented unpublished data on the role of airway DC in allergy (house dust mite) and asthma. His team showed that Charcot-Leyden (CL) crystals found in the mucus of patient lungs were derived from Galectin-10, produced by eosinophils. These crystals are associated with increased TNF and IL-6 production, and neutrophil and monocyte infiltration in the lungs. They observed that CL crystals are taken up by lung DC, CL crystals acting as an adjuvant, leading to a Th2 response. As Galectin-10 do not exist in rodent model, they used lamas to develop an antibody able to dissolve the CL crystals (Galectin-10 is allergenic only in its crystallized form), which also works in mucus of patients, giving hopes for potential therapy.

Last but not least, I would like to thank the CFCD for their financial support that allowed me to participate in this symposium. It has been a great opportunity for me to learn about the major advances made in the field of dendritic cells and to present our results during a poster session.