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

• Published in: Nature (London) 2017-02, Vol.542 (7639), p.110-114
• Main Authors: 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., Lederer, James A., Raychaudhuri, Soumya, Brenner, Michael B.
• Format: Article
• Language: English
• Subjects: 631/250/1619/554/1898/1270; 631/250/2152/2153/1291; 631/250/249/1313/498; 631/250/2520; 631/250/38; Arthritis, Rheumatoid - blood; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - pathology; Autoimmune diseases; B cells; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Cell Differentiation; Cell Movement; Chemokine CXCL13 - metabolism; Development and progression; Disease; Gene Expression Profiling; Health aspects; Humanities and Social Sciences; Humans; Inducible T-Cell Co-Stimulator Protein - metabolism; Interleukins - metabolism; letter; Lymphocytes; Macrophage-Activating Factors; multidisciplinary; Population; Positive Regulatory Domain I-Binding Factor 1; Programmed Cell Death 1 Receptor - metabolism; Proto-Oncogene Proteins c-bcl-6 - metabolism; Receptors, Chemokine - metabolism; Receptors, CXCR5 - deficiency; Receptors, CXCR5 - metabolism; Repressor Proteins - metabolism; Rheumatoid arthritis; Rodents; Science; Signaling Lymphocytic Activation Molecule Family - metabolism; Synovial Fluid - immunology; T cells; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - metabolism; T-Lymphocytes, Helper-Inducer - pathology; Transcription factors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature20810

The authors identify in patients with rheumatoid arthritis a pathogenic subset of CD4+ T cells that augments B cell responses within inflamed tissues. Peripheral helper T cells in rheumatoid arthritis Michael Brenner and colleagues identify a subset of pathogenically activated PD-1 hi CD4-positive T cells in patients with rheumatoid arthritis, and show that it promotes B-cell responses in tertiary lymphoid structures. The cells, which the authors designate as 'peripheral helper' T cells, differ from follicular helper cells in that they lack CXCR5, have altered BCL6 expression, and express chemokine receptors that direct migration to inflamed sites. 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 1 . 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 2 . 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.