Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity

Jellert T Gaublomme; Nir Yosef; Youjin Lee; Rona S Gertner; Li V Yang; Chuan Wu; Pier Paolo Pandolfi; Tak Mak; Rahul Satija; Alex K Shalek; Vijay K Kuchroo; Hongkun Park; Aviv Regev

doi:10.1016/j.cell.2015.11.009

Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity

Cell. 2015 Dec 3;163(6):1400-12. doi: 10.1016/j.cell.2015.11.009. Epub 2015 Nov 19.

Authors

Jellert T Gaublomme¹, Nir Yosef², Youjin Lee³, Rona S Gertner⁴, Li V Yang⁵, Chuan Wu⁶, Pier Paolo Pandolfi⁷, Tak Mak⁸, Rahul Satija⁹, Alex K Shalek¹⁰, Vijay K Kuchroo³, Hongkun Park¹¹, Aviv Regev¹²

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ Department of Internal Medicine, Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
⁶ 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.
⁷ 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.
⁸ Ontario Cancer Center, Princess Margaret Hospital, Toronto, ON M5G 2M9, Canada.
⁹ 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.
¹⁰ 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.
¹¹ 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: [email protected].
¹² 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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis Regulatory Proteins / metabolism
Carrier Proteins / metabolism
Central Nervous System / pathology
Encephalomyelitis, Autoimmune, Experimental / immunology
Encephalomyelitis, Autoimmune, Experimental / metabolism
Encephalomyelitis, Autoimmune, Experimental / pathology*
Gene Expression Profiling
Humans
Kruppel-Like Transcription Factors / metabolism
Lymph Nodes / pathology
Membrane Proteins / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Myelin-Oligodendrocyte Glycoprotein / metabolism
Peptide Fragments / metabolism
Promyelocytic Leukemia Zinc Finger Protein
Receptors, G-Protein-Coupled / metabolism
Receptors, Immunologic / metabolism
Receptors, Scavenger
Sequence Analysis, RNA*
Single-Cell Analysis*
Th17 Cells / immunology
Th17 Cells / metabolism*
Th17 Cells / pathology*

Substances

Apoptosis Regulatory Proteins
Carrier Proteins
Cd5l protein, mouse
Fcmr protein, mouse
GPR65 protein, mouse
Kruppel-Like Transcription Factors
Membrane Proteins
Myelin-Oligodendrocyte Glycoprotein
Peptide Fragments
Promyelocytic Leukemia Zinc Finger Protein
Receptors, G-Protein-Coupled
Receptors, Immunologic
Receptors, Scavenger
Zbtb16 protein, mouse
myelin oligodendrocyte glycoprotein (35-55)

Associated data

GEO/GSE74833

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding