title: Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity.
abstract: Extensive cellular heterogeneity exists within specific immune-cell subtypes classified as a single lineage, but its molecular underpinnings are rarely characterized at a genomic scale. Here, we use single-cell RNA-seq to investigate the molecular mechanisms governing heterogeneity and pathogenicity of Th17 cells isolated from the central nervous system (CNS) and lymph nodes (LN) at the peak of autoimmune encephalomyelitis (EAE) or differentiated in vitro under either pathogenic or non-pathogenic polarization conditions. Computational analysis relates a spectrum of cellular states in vivo to in-vitro-differentiated Th17 cells and unveils genes governing pathogenicity and disease susceptibility. Using knockout mice, we validate four new genes: Gpr65, Plzp, Toso, and Cd5l (in a companion paper). Cellular heterogeneity thus informs Th17 function in autoimmunity and can identify targets for selective suppression of pathogenic Th17 cells while potentially sparing non-pathogenic tissue-protective ones.
authors.affiliation: Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA; Department of Physics, Harvard University, 17 Oxford Street, Cambridge, MA 02138, USA.
authors.forename: Jellert T
authors.initials: JT
authors.lastname: Gaublomme
authors.affiliation: Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Department of Electrical Engineering and Computer Science and Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Nir
authors.initials: N
authors.lastname: Yosef
authors.affiliation: Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Youjin
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA; Department of Physics, Harvard University, 17 Oxford Street, Cambridge, MA 02138, USA.
authors.forename: Rona S
authors.initials: RS
authors.lastname: Gertner
authors.affiliation: Department of Internal Medicine, Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
authors.forename: Li V
authors.initials: LV
authors.lastname: Yang
authors.affiliation: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: Wu
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.affiliation: Ontario Cancer Center, Princess Margaret Hospital, Toronto, ON M5G 2M9, Canada.
authors.forename: Tak
authors.initials: T
authors.lastname: Mak
authors.affiliation: Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; New York Genome Center, New York, NY 10013, USA; Center for Genomics and Systems Biology, New York University, New York, NY 10012, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Satija
authors.affiliation: Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Institute for Medical Engineering and Science and Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA 02139, USA.
authors.forename: Alex K
authors.initials: AK
authors.lastname: Shalek
authors.affiliation: Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.affiliation: Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA; Department of Physics, Harvard University, 17 Oxford Street, Cambridge, MA 02138, USA. Electronic address: hongkun_park@harvard.edu.
authors.forename: Hongkun
authors.initials: H
authors.lastname: Park
authors.affiliation: Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Howard Hughes Medical Institute and David H. Koch Institute of Integrative Cancer Biology, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: aregev@broadinstitute.org.
authors.forename: Aviv
authors.initials: A
authors.lastname: Regev
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002490:Central Nervous System / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008198:Lymph Nodes / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D051116:Receptors, Scavenger; D017423:Sequence Analysis, RNA; D059010:Single-Cell Analysis; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C117272:Cd5l protein, mouse; C499656:Fcmr protein, mouse; C513337:GPR65 protein, mouse; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D043562:Receptors, G-Protein-Coupled; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; C513267:Zbtb16 protein, mouse; C445081:myelin oligodendrocyte glycoprotein (35-55)