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.

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
  • 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
  • Zbtb16 protein, mouse
  • myelin oligodendrocyte glycoprotein (35-55)

Associated data

  • GEO/GSE74833