title: Clonal expansion of CD4(+) cytotoxic T lymphocytes in patients with IgG4-related disease.
abstract: IgG4-related disease (IgG4-RD) is a systemic condition of unknown cause characterized by highly fibrotic lesions with dense lymphoplasmacytic infiltrates. CD4(+) T cells constitute the major inflammatory cell population in IgG4-RD lesions.
  
  
  
  We used an unbiased approach to characterize CD4(+) T-cell subsets in patients with IgG4-RD based on their clonal expansion and ability to infiltrate affected tissue sites.
  
  
  
  We used flow cytometry to identify CD4(+) effector/memory T cells in a cohort of 101 patients with IgG4-RD. These expanded cells were characterized by means of gene expression analysis and flow cytometry. Next-generation sequencing of the T-cell receptor β chain gene was performed on CD4(+)SLAMF7(+) cytotoxic T lymphocytes (CTLs) and CD4(+)GATA3(+) TH2 cells in a subset of patients to identify their clonality. Tissue infiltration by specific T cells was examined by using quantitative multicolor imaging.
  
  
  
  CD4(+) effector/memory T cells with a cytolytic phenotype were expanded in patients with IgG4-RD. Next-generation sequencing revealed prominent clonal expansions of these CD4(+) CTLs but not CD4(+)GATA3(+) memory TH2 cells in patients with IgG4-RD. The dominant T cells infiltrating a range of inflamed IgG4-RD tissue sites were clonally expanded CD4(+) CTLs that expressed SLAMF7, granzyme A, IL-1β, and TGF-β1. Clinical remission induced by rituximab-mediated B-cell depletion was associated with a reduction in numbers of disease-associated CD4(+) CTLs.
  
  
  
  IgG4-RD is prominently linked to clonally expanded IL-1β- and TGF-β1-secreting CD4(+) CTLs in both peripheral blood and inflammatory tissue lesions. These active, terminally differentiated, cytokine-secreting effector CD4(+) T cells are now linked to a human disease characterized by chronic inflammation and fibrosis.
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
authors.forename: Hamid
authors.initials: H
authors.lastname: Mattoo
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
authors.forename: Vinay S
authors.initials: VS
authors.lastname: Mahajan
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Mass; Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Fukuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Maehara
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Della-Torre
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
authors.forename: Zachary S
authors.initials: ZS
authors.lastname: Wallace
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
authors.forename: Maria
authors.initials: M
authors.lastname: Kulikova
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
authors.forename: Jefte M
authors.initials: JM
authors.lastname: Drijvers
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
authors.forename: Joe
authors.initials: J
authors.lastname: Daccache
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
authors.forename: Mollie N
authors.initials: MN
authors.lastname: Carruthers
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
authors.forename: Flavia V
authors.initials: FV
authors.lastname: Castelino
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
authors.forename: James R
authors.initials: JR
authors.lastname: Stone
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Mass. Electronic address: jhstone@partners.org.
authors.forename: John H
authors.initials: JH
authors.lastname: Stone
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Mass. Electronic address: pillai@helix.mgh.harvard.edu.
authors.forename: Shiv
authors.initials: S
authors.lastname: Pillai
mesh_terms: D000328:Adult; D000368:Aged; D016207:Cytokines / Q000276:immunology; D005260:Female; D006801:Humans; D007154:Immune System Diseases / Q000097:blood / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology*; D007668:Kidney / Q000166:cytology; D008168:Lung / Q000166:cytology; D008198:Lymph Nodes / Q000166:cytology; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009300:Nasal Septum / Q000166:cytology; D012187:Retroperitoneal Space; D013363:Submandibular Gland / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D016207:Cytokines; D007074:Immunoglobulin G
keywords: CD4(+) cytotoxic T cells; Fibrosis; IL-1β; IgG(4); IgG(4)-related disease; T(H)2 cells; rituximab