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Nature. 2017 Feb 1;542(7639):110-114. doi: 10.1038/nature20810.

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

Author information

1
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
2
Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2WB, UK.
3
Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
4
Program in Medical and Population Genetics, Broad Institute of Massachusetts Technical Institute and Harvard University, Cambridge, Massachusetts 02138, USA.
5
Partners Center for Personalized Genetic Medicine, Boston, Massachusetts 02115, USA.
6
Bioinformatics and Integrative Genomics, Harvard University, Cambridge, Massachusetts 02138, USA.
7
Biological and Biomedical Sciences, Harvard University, Cambridge, Massachusetts 02138, USA.
8
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York 10021, USA.
9
David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York 10021, USA.
10
Division of Immunology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
11
Division of Rheumatology, Hospital for Special Surgery, 535 E 70th Street, New York, New York 10021, USA.
12
Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York 10021, USA.
13
Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, New York 10021, USA.
14
Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
15
Reumatology Unit, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, S-171 76, Sweden.
16
Institute of Inflammation and Repair, University of Manchester, Manchester, M13 9PT, UK.

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-1hiCXCR5-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-1hiCXCR5- 'peripheral helper' T (TPH) cells that express factors enabling B-cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1hiCXCR5+ 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.

PMID:
28150777
PMCID:
PMC5349321
DOI:
10.1038/nature20810
[Indexed for MEDLINE]
Free PMC Article

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