TY - JOUR
T1 - Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis
AU - Rao, Deepak A.
AU - Gurish, Michael F.
AU - Marshall, Jennifer L.
AU - Slowikowski, Kamil
AU - Fonseka, Chamith Y.
AU - Liu, Yanyan
AU - Donlin, Laura T.
AU - Henderson, Lauren A.
AU - Wei, Kevin
AU - Mizoguchi, Fumitaka
AU - Teslovich, Nikola C.
AU - Weinblatt, Michael E.
AU - Massarotti, Elena M.
AU - Coblyn, Jonathan S.
AU - Helfgott, Simon M.
AU - Lee, Yvonne C.
AU - Todd, Derrick J.
AU - Bykerk, Vivian P.
AU - Goodman, Susan M.
AU - Pernis, Alessandra B.
AU - Ivashkiv, Lionel B.
AU - Karlson, Elizabeth W.
AU - Nigrovic, Peter A.
AU - Filer, Andrew
AU - Buckley, Christopher D.
AU - Lederer, James A.
AU - Raychaudhuri, Soumya
AU - Brenner, Michael B.
PY - 2017/2/2
Y1 - 2017/2/2
N2 - 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-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 TPH cells. TPH cells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues.
AB - 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-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 TPH cells. TPH cells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues.
KW - PD-1
KW - mass cytometry
KW - follicular helper T cells
KW - rheumatoid arthritis
KW - plasma cells
KW - CCR2
KW - autoimmunity
KW - antibodies
KW - follicular T-helper cells
KW - translational immunology
U2 - 10.1038/nature20810
DO - 10.1038/nature20810
M3 - Article
SN - 0028-0836
VL - 542
SP - 110
EP - 114
JO - Nature
JF - Nature
IS - 7639
ER -