The human tissue-resident CCR5+ T cell compartment maintains protective and functional properties during inflammation

Sci Transl Med. 2019 Dec 4;11(521):eaaw8718. doi: 10.1126/scitranslmed.aaw8718.

Abstract

CCR5 is thought to play a central role in orchestrating migration of cells in response to inflammation. CCR5 antagonists can reduce inflammatory disease processes, which has led to an increased interest in using CCR5 antagonists in a wide range of inflammation-driven diseases. Paradoxically, these antagonists appear to function without negatively affecting host immunity at barrier sites. We reasoned that the resolution to this paradox may lie in the CCR5+ T cell populations that permanently reside in tissues. We used a single-cell analysis approach to examine the human CCR5+ T cell compartment in the blood, healthy, and inflamed mucosal tissues to resolve these seemingly contradictory observations. We found that 65% of the CD4 tissue-resident memory T (TRM) cell compartment expressed CCR5. These CCR5+ TRM cells were enriched in and near the epithelial layer and not only limited to TH1-type cells but also contained a large TH17-producing and a stable regulatory T cell population. The CCR5+ TRM compartment was stably maintained even in inflamed tissues including the preservation of TH17 and regulatory T cell populations. Further, using tissues from the CHARM-03 clinical trial, we found that CCR5+ TRM are preserved in human mucosal tissue during treatment with the CCR5 antagonist Maraviroc. Our data suggest that the human CCR5+ TRM compartment is functionally and spatially equipped to maintain barrier immunity even in the absence of CCR5-mediated, de novo T cell recruitment from the periphery.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, CD / metabolism
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Compartmentation* / drug effects
  • Cytokines / biosynthesis
  • Female
  • Humans
  • Inflammation / immunology*
  • Lectins, C-Type / metabolism
  • Lymphocyte Subsets / drug effects
  • Lymphocyte Subsets / immunology
  • Male
  • Maraviroc / pharmacology
  • Middle Aged
  • Mouth Mucosa / drug effects
  • Mouth Mucosa / immunology
  • Mouth Mucosa / pathology
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, CCR5 / metabolism*
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • Th17 Cells / drug effects
  • Th17 Cells / immunology
  • Transcriptome / genetics
  • Young Adult

Substances

  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CCR5 protein, human
  • CD69 antigen
  • Cytokines
  • Lectins, C-Type
  • Receptors, Antigen, T-Cell
  • Receptors, CCR5
  • Maraviroc