Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis

Deepak A Rao, Michael F Gurish, Jennifer L Marshall, Kamil Slowikowski, Chamith Y Fonseka, Yanyan Liu, Laura T Donlin, Lauren A Henderson, Kevin Wei, Fumitaka Mizoguchi, Nikola C Teslovich, Michael E Weinblatt, Elena M Massarotti, Jonathan S Coblyn, Simon M Helfgott, Yvonne C Lee, Derrick J Todd, Vivian P Bykerk, Susan M Goodman, Alessandra B PernisLionel B Ivashkiv, Elizabeth W Karlson, Peter A Nigrovic, Andrew Filer, Christopher D Buckley, James A Lederer, Soumya Raychaudhuri, Michael B Brenner

Research output: Contribution to journalArticlepeer-review

Abstract

CD4(+) T cells are central mediators of autoimmune pathology; however, defining their key effector functions in specific autoimmune diseases remains challenging. Pathogenic CD4(+) T cells within affected tissues may be identified by expression of markers of recent activation. Here we use mass cytometry to analyse activated T cells in joint tissue from patients with rheumatoid arthritis, a chronic immune-mediated arthritis that affects up to 1% of the population. This approach revealed a markedly expanded population of PD-1(hi)CXCR5(-)CD4(+) T cells in synovium of patients with rheumatoid arthritis. However, these cells are not exhausted, despite high PD-1 expression. Rather, using multidimensional cytometry, transcriptomics, and functional assays, we define a population of PD-1(hi)CXCR5(-) 'peripheral helper' T (TPH) cells that express factors enabling B-cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1(hi)CXCR5(+) T follicular helper cells, TPH cells induce plasma cell differentiation in vitro through IL-21 secretion and SLAMF5 interaction (refs 3, 4). However, global transcriptomics highlight differences between TPH cells and T follicular helper cells, including altered expression of BCL6 and BLIMP1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in TPH cells. TPH cells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues.

Original languageEnglish
Pages (from-to)110-114
Number of pages5
JournalNature
Volume542
Issue number7639
DOIs
Publication statusPublished - 1 Feb 2017

Keywords

  • Arthritis, Rheumatoid
  • B-Lymphocytes
  • Cell Differentiation
  • Cell Movement
  • Chemokine CXCL13
  • Gene Expression Profiling
  • Humans
  • Inducible T-Cell Co-Stimulator Protein
  • Interleukins
  • Macrophage-Activating Factors
  • Programmed Cell Death 1 Receptor
  • Proto-Oncogene Proteins c-bcl-6
  • Receptors, CXCR5
  • Receptors, Chemokine
  • Repressor Proteins
  • Signaling Lymphocytic Activation Molecule Family
  • Synovial Fluid
  • T-Lymphocytes, Helper-Inducer
  • Journal Article

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