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

Hamid Mattoo, Vinay S. Mahajan, takashi maehara, Vikram Deshpande, Emanuel Della-Torre, Zachary S. Wallace, Maria Kulikova, Jefte M. Drijvers, Joe Daccache, Mollie N. Carruthers, Flavia V. Castelino, James R. Stone, John H. Stone, Shiv Pillai

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113 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)825-838
Number of pages14
JournalJournal of Allergy and Clinical Immunology
Volume138
Issue number3
DOIs
Publication statusPublished - Sep 1 2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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    Mattoo, H., Mahajan, V. S., maehara, T., Deshpande, V., Della-Torre, E., Wallace, Z. S., Kulikova, M., Drijvers, J. M., Daccache, J., Carruthers, M. N., Castelino, F. V., Stone, J. R., Stone, J. H., & Pillai, S. (2016). Clonal expansion of CD4+ cytotoxic T lymphocytes in patients with IgG4-related disease. Journal of Allergy and Clinical Immunology, 138(3), 825-838. https://doi.org/10.1016/j.jaci.2015.12.1330