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 activation1. 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 population2. This approach revealed a markedly expanded population of PD-1hiCXCR5CD4+ 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.

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This work was supported by T32 AR007530-31 and the William Docken Inflammatory Autoimmune Disease Fund (to M.B.B.), Mallinckrodt Research Fellowship (to D.A.R.), R01 AR064850-03 (to Y.C.L.), NIH 5U01GM092691-05, 1U19 AI111224-01 and Doris Duke Charitable Foundation Grant #2013097 (to S.R.), Rheumatology Research Foundation Scientist Development Award (to L.A.H.), K01 AR066063 (to L.T.D.), Arthritis Research UK programme grant #19791 (to C.D.B.), and Arthritis Research UK Clinician Scientist Fellowship #18547 (to A.F.). J.L.M was supported by the FP7-HEALTH-F2-2012-305549 EuroTEAM. P.A.N. was supported by P30 AR070253 and the Fundación Bechara. We thank A. Chicoine and the BWH Human Immunology Center Flow Cytometry Core for assistance with cell sorting.

Author information


  1. Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA

    • Deepak A. Rao
    • , Michael F. Gurish
    • , Kamil Slowikowski
    • , Chamith Y. Fonseka
    • , Yanyan Liu
    • , 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
    • , Elizabeth W. Karlson
    • , Peter A. Nigrovic
    • , Soumya Raychaudhuri
    •  & Michael B. Brenner
  2. Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2WB, UK

    • Jennifer L. Marshall
    • , Andrew Filer
    •  & Christopher D. Buckley
  3. Division of Genetics, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA

    • Kamil Slowikowski
    • , Chamith Y. Fonseka
    • , Nikola C. Teslovich
    •  & Soumya Raychaudhuri
  4. Program in Medical and Population Genetics, Broad Institute of Massachusetts Technical Institute and Harvard University, Cambridge, Massachusetts 02138, USA

    • Kamil Slowikowski
    • , Chamith Y. Fonseka
    • , Nikola C. Teslovich
    •  & Soumya Raychaudhuri
  5. Partners Center for Personalized Genetic Medicine, Boston, Massachusetts 02115, USA

    • Kamil Slowikowski
    •  & Soumya Raychaudhuri
  6. Bioinformatics and Integrative Genomics, Harvard University, Cambridge, Massachusetts 02138, USA

    • Kamil Slowikowski
    •  & Chamith Y. Fonseka
  7. Biological and Biomedical Sciences, Harvard University, Cambridge, Massachusetts 02138, USA

    • Chamith Y. Fonseka
  8. Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York 10021, USA

    • Laura T. Donlin
    •  & Lionel B. Ivashkiv
  9. David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York 10021, USA

    • Laura T. Donlin
    • , Alessandra B. Pernis
    •  & Lionel B. Ivashkiv
  10. Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts 02115, USA

    • Lauren A. Henderson
    •  & Peter A. Nigrovic
  11. Division of Rheumatology, Hospital for Special Surgery, 535 E 70th Street, New York, New York 10021, USA

    • Vivian P. Bykerk
    •  & Susan M. Goodman
  12. Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York 10021, USA

    • Vivian P. Bykerk
    • , Susan M. Goodman
    •  & Alessandra B. Pernis
  13. Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, New York 10021, USA

    • Alessandra B. Pernis
  14. Department of Surgery, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA

    • James A. Lederer
  15. Reumatology Unit, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, S-171 76, Sweden

    • Soumya Raychaudhuri
  16. Institute of Inflammation and Repair, University of Manchester, Manchester, M13 9PT, UK

    • Soumya Raychaudhuri


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D.A.R conceived the project, performed experiments, analysed data, and wrote the manuscript. M.F.G., Y.L., N.T., and F.M. performed experiments and analysed data. K.S. analysed transcriptomic data. C.F. analysed mass cytometry data. J.L.M. performed immunofluorescence microscopy. J.A.L. assisted with mass cytometry. K.W., L.A.H., P.A.N., M.E.W., Y.C.L., J.S.C., D.J.T., E.M.M., S.M.H., E.W.K., L.T.D., V.P.B., L.B.I., S.M.G., A.B.P., A.F. and C.D.B participated in study design, patient recruitment and sample acquisition. M.B.B. and S.R. conceived the project, supervised the work, analysed data, and co-wrote the manuscript. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Deepak A. Rao or Michael B. Brenner.

Reviewer Information Nature thanks J. Craft, S. Fillatreau and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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