PMID- 31668803 OWN - NLM STAT- MEDLINE DCOM- 20200527 LR - 20210401 IS - 1097-4172 (Electronic) IS - 0092-8674 (Print) IS - 0092-8674 (Linking) VI - 179 IP - 4 DP - 2019 Oct 31 TI - Transcriptional Basis of Mouse and Human Dendritic Cell Heterogeneity. PG - 846-863.e24 LID - S0092-8674(19)31116-X [pii] LID - 10.1016/j.cell.2019.09.035 [doi] AB - Dendritic cells (DCs) play a critical role in orchestrating adaptive immune responses due to their unique ability to initiate T cell responses and direct their differentiation into effector lineages. Classical DCs have been divided into two subsets, cDC1 and cDC2, based on phenotypic markers and their distinct abilities to prime CD8 and CD4 T cells. While the transcriptional regulation of the cDC1 subset has been well characterized, cDC2 development and function remain poorly understood. By combining transcriptional and chromatin analyses with genetic reporter expression, we identified two principal cDC2 lineages defined by distinct developmental pathways and transcriptional regulators, including T-bet and RORgammat, two key transcription factors known to define innate and adaptive lymphocyte subsets. These novel cDC2 lineages were characterized by distinct metabolic and functional programs. Extending our findings to humans revealed conserved DC heterogeneity and the presence of the newly defined cDC2 subsets in human cancer. CI - Copyright (c) 2019 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Brown, Chrysothemis C AU - Brown CC AD - Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Infection, Inflammation and Rheumatology Section, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK. Electronic address: brownc10@mskcc.org. FAU - Gudjonson, Herman AU - Gudjonson H AD - Infection, Inflammation and Rheumatology Section, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK. FAU - Pritykin, Yuri AU - Pritykin Y AD - Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Deep, Deeksha AU - Deep D AD - Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Lavallee, Vincent-Philippe AU - Lavallee VP AD - Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Mendoza, Alejandra AU - Mendoza A AD - Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Fromme, Rachel AU - Fromme R AD - Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Mazutis, Linas AU - Mazutis L AD - Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Ariyan, Charlotte AU - Ariyan C AD - Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Ludwig Center at Memorial Sloan Kettering Cancer Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Leslie, Christina AU - Leslie C AD - Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Pe'er, Dana AU - Pe'er D AD - Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Rudensky, Alexander Y AU - Rudensky AY AD - Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Ludwig Center at Memorial Sloan Kettering Cancer Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: rudenska@mskcc.org. LA - eng GR - 201483/Z/16/Z/WT_/Wellcome Trust/United Kingdom GR - P30 CA008748/CA/NCI NIH HHS/United States GR - U54 CA209975/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20191024 PL - United States TA - Cell JT - Cell JID - 0413066 RN - 0 (Chromatin) SB - IM MH - Adaptive Immunity/genetics MH - Animals MH - Cell Differentiation/*genetics/immunology MH - Cell Lineage/*genetics MH - Chromatin/genetics MH - Dendritic Cells/immunology MH - Gene Expression Regulation, Developmental MH - *Genetic Heterogeneity MH - Humans MH - Immunity, Innate/genetics MH - Lymphocyte Subsets/immunology/metabolism MH - Mice MH - Neoplasms/genetics/*immunology MH - T-Lymphocytes/immunology/metabolism MH - Transcription, Genetic/immunology PMC - PMC6838684 OTO - NOTNLM OT - ATAC-sequencing OT - T-bet OT - dendritic cells OT - myeloid cells OT - single-cell RNA-sequencing OT - transcriptional regulation COIS- The authors declare no competing interests. EDAT- 2019/11/02 06:00 MHDA- 2020/05/28 06:00 PMCR- 2019/10/31 CRDT- 2019/11/01 06:00 PHST- 2019/03/25 00:00 [received] PHST- 2019/07/12 00:00 [revised] PHST- 2019/09/27 00:00 [accepted] PHST- 2019/11/01 06:00 [entrez] PHST- 2019/11/02 06:00 [pubmed] PHST- 2020/05/28 06:00 [medline] PHST- 2019/10/31 00:00 [pmc-release] AID - S0092-8674(19)31116-X [pii] AID - 10.1016/j.cell.2019.09.035 [doi] PST - ppublish SO - Cell. 2019 Oct 31;179(4):846-863.e24. doi: 10.1016/j.cell.2019.09.035. Epub 2019 Oct 24.