Poster Presentation 18th International Symposium on Dendritic Cells 2026

Single-cell multi-omics of human dendritic cell differentiation reveals subtype-specific disease risk mechanisms (#214)

Ofir Cohn 1 2 3 4 , Chen Weng 1 2 3 4 , Tianyi Ye 1 2 3 4 , Anna-Lena Neehus 1 2 3 4 , Chun-Jie Guo 1 2 3 4 , Laila Barakat Norford 1 2 3 4 5 , Emily Kao 6 , Vijay G. Sankaran 1 2 3 4
  1. Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
  2. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
  3. Broad Institute of MIT and Harvard, Cambridge, MA, USA
  4. Howard Hughes Medical Institute, Boston, MA, USA
  5. PhD Program in Biomedical Informatics, Harvard Medical School, Boston, MA, USA
  6. University of Illinois Chicago, Chicago, IL, USA

Defining the underlying cell types and mechanisms through which genetic variation operates is essential to fully understand the biological basis of disease. While the clinical relevance of human dendritic cells (DCs) in mediating immune responses is well-established, their rarity and our limited knowledge of their regulatory networks have hampered the ability to map inherited disease-associated variation to specific human DC subsets across different differentiation stages. To address these limitations, we employed a tractable human DC differentiation system from hematopoietic stem and progenitor cells (HSPCs) to deeply profile all DC subsets and their precursors, enabling single-cell multi-omic insights into these cells and their development. These high-resolution data enabled the identification of dynamic gene regulatory networks (GRNs) governing subset fate specification. More importantly, by integrating this regulatory architecture with fine-mapped variants from hundreds of complex-trait genome-wide association studies (GWASs), we systematically mapped inflammatory, autoimmune, and oncologic disease risk to subset-specific variant-to-gene mechanisms. The results of these analyses highlight unappreciated mechanisms of complex diseases, including an inflammatory bowel disease (IBD) risk variant linked to a CD40 enhancer specifically in mature DCs and the identification of a highly protective type 1 diabetes (T1D) variant linked to Cathepsin H (CTSH) within cDC2s. We provide a deeper mechanistic understanding of the pleiotropic role of pDCs in immune function, demonstrating that a phospholipase D family member 4 (PLD4) variant drives pDC-specific disease predisposition to developing systemic lupus erythematosus (SLE) and other autoimmune disorders by increasing TLR7-mediated responses. Together, we define a key and underappreciated role of human DCs in mediating the consequences of inherited genetic variation on a range of complex disorders, expanding the relevance of these rare, yet critical, immune cells in human disease.