SummaryDendritic cells (DCs) play a key role in orchestrating adaptive immune responses. In human blood, three distinct subsets exist: plasmacytoid DCs (pDCs) and BDCA3+ and CD1c+ myeloid DCs. In addition, a DC-like CD16+ monocyte has been reported. Although RNA-expression profiles have been previously compared, protein expression data may provide a different picture. Here, we exploited label-free quantitative mass spectrometry to compare and identify differences in primary human DC subset proteins. Moreover, we integrated these proteomic data with existing mRNA data to derive robust cell-specific expression signatures with more than 400 differentially expressed proteins between subsets, forming a solid basis for investigation of subset-specific functions. We illustrated this by extracting subset identification markers and by demonstrating that pDCs lack caspase-1 and only express low levels of other inflammasome-related proteins. In accordance, pDCs were incapable of interleukin (IL)-1β secretion in response to ATP.

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Renal tract defects and autism spectrum disorder (ASD) deficits represent the phenotypic core of the 19q12 deletion syndrome caused by the loss of one copy of the TSHZ3 gene. While a proportion of Tshz3 heterozygous (Tshz3+/lacZ) mice display ureteral defects, no kidney defects have been reported in these mice. The purpose of this study was to characterize the expression of Tshz3 in adult kidney as well as the renal physiological consequences of embryonic haploinsufficiency of Tshz3 by analyzing the morphology and function of Tshz3 heterozygous adult kidney. Here, we described Tshz3 expression in the smooth muscle and stromal cells lining the renal pelvis, the papilla and glomerular endothelial cells (GEnCs) of the adult kidney. Histological analysis showed that Tshz3+/lacZ adult kidney had an average of 29% fewer glomeruli than wild type kidney. Transmission electron microscopy (TEM) of Tshz3+/lacZ glomeruli revealed ultrastructural defects. Compared to wild type, Tshz3+/lacZ mice showed no difference in their urine parameters but lower blood urea, phosphates, magnesium and potassium at 2 months of age. At the molecular level, transcriptome analysis identified differentially expressed genes related to inflammatory processes in Tshz3+/lacZ compare to wild type (WT; control) adult kidneys. Lastly, analysis of the urinary peptidome revealed 33 peptides associated with Tshz3+/lacZ adult mice. These results provide the first evidence that in the mouse Tshz3 haploinsufficiency leads to cellular, molecular and functional abnormalities in the adult mouse kidney.

Dendritic cells (DCs) play a key role in the orchestration of antitumor immune responses. The cDC1 subset was demonstrated as essential for tumor control and response to immunotherapies in mice, but its precise role in human is largely unexplored. In our study, we combined the analysis of large cohorts of fresh breast and ovarian primary tumors and of public transcriptomic data sets to elucidate human cDC1 functions and clinical impact compared with other DC subsets. We identified a key role for intratumoral cDC1 in producing selectively type III interferon (IFN-III), strongly associated with cytokines and chemokines promoting cytotoxic immune cell recruitment and activation. Of utmost importance, we also revealed a positive impact of IFN-III and cDC1 on patient outcome in many human cancers and identified TLR3-triggering as a therapeutic strategy to trigger IFN-III production by tumor-associated cDC1. These data may pave the way for new IFN or cDC1-targeting antitumor therapies. Citation Format: Margaux Hubert, Coline Couillault, Thien Phong Vu Manh, Vincent Ollion, Helene Lopez-Mestre, Nabil Rahmouni, Janice KIielbassa, Celine Rodriguez, Christophe Sajous, Benoit Dumont, Anne-Claire Doffin, Isabelle Treilleux, Olivier Tredan, Marc Dalod, Nathalie BendrissS-Vermare, Christophe Caux, Jenny Valladeau-Guilemomd. IFN-III is selectively produced by cDC1 and predicts good clinical outcome in human breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A70.