Skin and gut imprinted helper T cell subsets exhibit distinct functional phenotypes in central nervous system autoimmunity

Nat Immunol. 2021 Jul;22(7):880-892. doi: 10.1038/s41590-021-00948-8. Epub 2021 Jun 7.

Abstract

Multidimensional single-cell analyses of T cells have fueled the debate about whether there is extensive plasticity or 'mixed' priming of helper T cell subsets in vivo. Here, we developed an experimental framework to probe the idea that the site of priming in the systemic immune compartment is a determinant of helper T cell-induced immunopathology in remote organs. By site-specific in vivo labeling of antigen-specific T cells in inguinal (i) or gut draining mesenteric (m) lymph nodes, we show that i-T cells and m-T cells isolated from the inflamed central nervous system (CNS) in a model of multiple sclerosis (MS) are distinct. i-T cells were Cxcr6+, and m-T cells expressed P2rx7. Notably, m-T cells infiltrated white matter, while i-T cells were also recruited to gray matter. Therefore, we propose that the definition of helper T cell subsets by their site of priming may guide an advanced understanding of helper T cell biology in health and disease.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Adoptive Transfer
  • Animals
  • Autoimmunity* / drug effects
  • Brain / drug effects
  • Brain / immunology*
  • Brain / metabolism
  • Calcium Signaling
  • Cell Lineage*
  • Cerebrospinal Fluid / immunology
  • Cerebrospinal Fluid / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Fingolimod Hydrochloride / pharmacology
  • Gene Expression Profiling
  • Genes, T-Cell Receptor
  • HEK293 Cells
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Intestines / drug effects
  • Intestines / immunology*
  • Intravital Microscopy
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Fluorescence
  • Multiple Sclerosis, Relapsing-Remitting / genetics
  • Multiple Sclerosis, Relapsing-Remitting / immunology
  • Multiple Sclerosis, Relapsing-Remitting / metabolism
  • Phenotype
  • Prospective Studies
  • RNA-Seq
  • Receptors, CXCR6 / genetics
  • Receptors, CXCR6 / metabolism
  • Receptors, Purinergic P2X7 / genetics
  • Receptors, Purinergic P2X7 / metabolism
  • Single-Cell Analysis
  • Skin / drug effects
  • Skin / immunology*
  • Skin / metabolism
  • T-Lymphocytes, Helper-Inducer / drug effects
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism
  • T-Lymphocytes, Helper-Inducer / transplantation
  • Transcriptome

Substances

  • Cxcr6 protein, mouse
  • Immunosuppressive Agents
  • P2rx7 protein, mouse
  • Receptors, CXCR6
  • Receptors, Purinergic P2X7
  • Fingolimod Hydrochloride