Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis
Open accessAbstract
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 (T PH) cells that express factors enabling B-cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1 hi CXCR5+ T follicular helper cells, T PH cells induce plasma cell differentiation in vitro through IL-21 secretion and SLAMF5 interaction (refs 3, 4). However, global transcriptomics highlight differences between T PH 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 T PH cells. T PH cells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues.
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In vitro expanded AQP4-specific T cells represent Tph-like rather than Tfh-like features.
“Thus, in vitro expanded AQP4-specific T cells represent Tph-like rather than Tfh-like features, as identified in AID patients before. 16,17,54”
From Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases (2024) · cites this paper as [54]
A similar Tph phenotype is present in rheumatoid arthritis and in autoantigen-specific T cells isolated via ARTE from patients with AIH.
“A similar Tph phenotype is present in rheumatoid arthritis 54 and in autoantigen-specific T cells isolated via ARTE from patients with AIH.”
From Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases (2024) · cites this paper as [54]
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- Authors
- Rao, D. A., Gurish, M. F., Marshall, J. L., Slowikowski, K., Fonseka, C. Y., Liu, Y., Donlin, L. T., Henderson, L. A., Wei, K., Mizoguchi, F., Teslovich, N. C., Weinblatt, M. E., Massarotti, E. M., Coblyn, J. S., Helfgott, S. M., Lee, Y. C., Todd, D. J., Bykerk, V. P., Goodman, S. M., Pernis, A. B., Ivashkiv, L. B., Karlson, E. W., Nigrovic, P. A., Filer, A., Buckley, C. D., Lederer, J. A., Raychaudhuri, S., & Brenner, M. B.
- Affiliations
- Brigham and Women's Hospital (US)
- Queen Elizabeth Hospital Birmingham (GB)
- Broad Institute (US)
- Hospital for Special Surgery (US)
- Boston Children's Hospital (US)
- Corresponding author
- Rao, Deepak A.
- Brenner, Michael B.
- ORCID
- Rao, Deepak A.
- Gurish, Michael F.
- Marshall, Jennifer L.
- Slowikowski, Kamil
- Fonseka, Chamith Y.
- Liu, Yanyan
- Donlin, Laura T.
- Henderson, Lauren A.
- Wei, Kevin
- Mizoguchi, Fumitaka
- Teslovich, Nikola C.
- Weinblatt, Michael E.
- Massarotti, Elena M.
- Coblyn, Jonathan S.
- Helfgott, Simon M.
- Lee, Yvonne C.
- Todd, Derrick J.
- Bykerk, Vivian P.
- Goodman, Susan M.
- Pernis, Alessandra B.
- Ivashkiv, Lionel B.
- Karlson, Elizabeth W.
- Nigrovic, Peter A.
- Filer, Andrew
- Buckley, Christopher D.
- Raychaudhuri, Soumya
- Brenner, Michael B.
- Venue
- Nature
- Published
- 2017-02-02
- Volume
- 542
- Issue
- 7639
- Pages
- 110-114
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5349321
- OpenAlex
- W2585122285
- Cited by
- 1,125
- References
- 5
- Citations by year
- 2026: 106 · 2025: 148 · 2024: 147 · 2023: 134 · 2022: 126 · 2021: 139 · 2020: 110 · 2019: 102 · 2018: 74 · 2017: 38
- FWCI
- 77.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Funders
- Versus Arthritis (19791, 20088, 18547)
- National Institutes of Health (5r01ar063759-07, 5r01ar048114-08)
- National Human Genome Research Institute (U01HG009379)
- National Institute of General Medical Sciences (U01GM092691)
- National Institute of Allergy and Infectious Diseases (U19AI111224)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-AR048114, L40 AR065238, R01AR065538, K01AR066063, UH2AR067691, T32AR007530, R01AR064850, P30AR070253, R01AR046713, R01-AR063759)
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- rheumatoid arthritis, peripheral helper T cells, B cell response, tertiary lymphoid structures, synovium, T follicular helper cells, IL-21, BCL6, chemokine receptors, CCR2, CX3CR1, CCR5, plasma cell differentiation, antibody production, T cell exhaustion
- MeSH terms
- Signaling Lymphocytic Activation Molecule Family, Positive Regulatory Domain I-Binding Factor 1, Interleukin-21, Arthritis, Rheumatoid, B-Lymphocytes, Cell Differentiation, Cell Movement, T-Lymphocytes, Helper-Inducer, Humans, Interleukins, Repressor Proteins, Synovial Fluid, Macrophage-Activating Factors, Receptors, Chemokine, Gene Expression Profiling, Proto-Oncogene Proteins c-bcl-6, Receptors, CXCR5, Chemokine CXCL13, Inducible T-Cell Co-Stimulator Protein, Programmed Cell Death 1 Receptor
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