Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis.
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, TPHcells induce plasma cell differentiation in vitro through IL-21 secretion and SLAMF5 interaction (refs 3, 4). However, global transcriptomics highlight differences between TPHcells 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 TPHcells. TPHcells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues.
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Deepak A
DA
Rao
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Michael F
MF
Gurish
Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2WB, UK.
Jennifer L
JL
Marshall
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Program in Medical and Population Genetics, Broad Institute of Massachusetts Technical Institute and Harvard University, Cambridge, Massachusetts 02138, USA.|Partners Center for Personalized Genetic Medicine, Boston, Massachusetts 02115, USA.|Bioinformatics and Integrative Genomics, Harvard University, Cambridge, Massachusetts 02138, USA.
Kamil
K
Slowikowski
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Program in Medical and Population Genetics, Broad Institute of Massachusetts Technical Institute and Harvard University, Cambridge, Massachusetts 02138, USA.|Bioinformatics and Integrative Genomics, Harvard University, Cambridge, Massachusetts 02138, USA.|Biological and Biomedical Sciences, Harvard University, Cambridge, Massachusetts 02138, USA.
Chamith Y
CY
Fonseka
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Yanyan
Y
Liu
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York 10021, USA.|David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York 10021, USA.
Laura T
LT
Donlin
Division of Immunology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
Lauren A
LA
Henderson
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Kevin
K
Wei
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Fumitaka
F
Mizoguchi
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Program in Medical and Population Genetics, Broad Institute of Massachusetts Technical Institute and Harvard University, Cambridge, Massachusetts 02138, USA.
Nikola C
NC
Teslovich
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Michael E
ME
Weinblatt
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Elena M
EM
Massarotti
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Jonathan S
JS
Coblyn
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Simon M
SM
Helfgott
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Yvonne C
YC
Lee
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Derrick J
DJ
Todd
Division of Rheumatology, Hospital for Special Surgery, 535 E 70th Street, New York, New York 10021, USA.|Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York 10021, USA.
Vivian P
VP
Bykerk
Division of Rheumatology, Hospital for Special Surgery, 535 E 70th Street, New York, New York 10021, USA.|Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York 10021, USA.
Susan M
SM
Goodman
David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York 10021, USA.|Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York 10021, USA.|Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, New York 10021, USA.
Alessandra B
AB
Pernis
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York 10021, USA.|David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York 10021, USA.
Lionel B
LB
Ivashkiv
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Elizabeth W
EW
Karlson
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Division of Immunology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
Peter A
PA
Nigrovic
Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2WB, UK.
Andrew
A
Filer
Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2WB, UK.
Christopher D
CD
Buckley
Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
James A
JA
Lederer
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Program in Medical and Population Genetics, Broad Institute of Massachusetts Technical Institute and Harvard University, Cambridge, Massachusetts 02138, USA.|Partners Center for Personalized Genetic Medicine, Boston, Massachusetts 02115, USA.|Reumatology Unit, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, S-171 76, Sweden.|Institute of Inflammation and Repair, University of Manchester, Manchester, M13 9PT, UK.
Soumya
S
Raychaudhuri
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Michael B
MB
Brenner
D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology* / Q000473:pathology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation; D002465:Cell Movement; D054382:Chemokine CXCL13 / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D016215:Macrophage-Activating Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism; D054380:Receptors, CXCR5 / Q000172:deficiency / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D000071176:Signaling Lymphocytic Activation Molecule Family / Q000378:metabolism; D013582:Synovial Fluid / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D000098546:Interleukin-21
C084103:BCL6 protein, human; C498970:CD84 protein, human; C110663:CXCL13 protein, human; C095085:CXCR5 protein, human; D054382:Chemokine CXCL13; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D007378:Interleukins; D016215:Macrophage-Activating Factors; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D051560:Proto-Oncogene Proteins c-bcl-6; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine; D012097:Repressor Proteins; D000071176:Signaling Lymphocytic Activation Molecule Family; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1; D000098546:Interleukin-21