Clonal expansion of CD4(+) cytotoxic T lymphocytes in patients with IgG4-related disease

J Allergy Clin Immunol. 2016 Sep;138(3):825-838. doi: 10.1016/j.jaci.2015.12.1330. Epub 2016 Mar 11.


Background: 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.

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: CD4(+) cytotoxic T cells; Fibrosis; IL-1β; IgG(4); IgG(4)-related disease; T(H)2 cells; rituximab.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Cytokines / immunology
  • Female
  • Humans
  • Immune System Diseases / blood
  • Immune System Diseases / immunology*
  • Immunoglobulin G / blood
  • Immunoglobulin G / immunology*
  • Kidney / cytology
  • Lung / cytology
  • Lymph Nodes / cytology
  • Lymphocyte Count
  • Male
  • Middle Aged
  • Nasal Septum / cytology
  • Retroperitoneal Space
  • Submandibular Gland / cytology
  • T-Lymphocytes, Cytotoxic / immunology*


  • Cytokines
  • Immunoglobulin G