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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 ? 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-1?, and TGF-?1. 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-1?- and TGF-?1-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.

SUBMITTER: Mattoo H

PROVIDER: S-EPMC5014627 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Mattoo Hamid H Mahajan Vinay S VS Maehara Takashi T Deshpande Vikram V Della-Torre Emanuel E Wallace Zachary S ZS Kulikova Maria M Drijvers Jefte M JM Daccache Joe J Carruthers Mollie N MN Castelino Flavia V FV Stone James R JR Stone John H JH Pillai Shiv S

The Journal of allergy and clinical immunology 20160311 3

<h4>Background</h4>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.<h4>Objective</h4>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.<h4>Methods</h4>We used flow cytometry to identify C ...[more]

PMID: 26971690

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Project description:OBJECTIVE:An unconventional population of CD4+ signaling lymphocytic activation molecule family member 7-positive (SLAMF7+) cytotoxic effector memory T (TEM ) cells (CD4+ cytotoxic T lymphocytes [CTLs]) has been linked causally to IgG4-related disease (IgG4-RD). Glucocorticoids represent the first-line therapeutic approach in patients with IgG4-RD, but their mechanism of action in this specific condition remains unknown. We undertook this study to determine the impact of glucocorticoids on CD4+ CTLs in IgG4-RD. METHODS:Expression of CD8?, granzyme A, perforin, and SLAMF7 within the effector memory compartment of CD45RO+ (TEM ) and CD45RA+ effector memory T (TEMRA ) CD4+ cells was quantified by flow cytometry in 18 patients with active IgG4-RD, both at baseline and after 6 months of glucocorticoid treatment. Eighteen healthy subjects were studied as controls. Next-generation sequencing of the T cell receptor ?- and ?-chain gene was performed on circulating CD4+ CTLs from patients with IgG4-RD before and after treatment and in affected tissues. RESULTS:Circulating CD4+ TEM and TEMRA cells were not expanded in IgG4-RD patients compared to healthy controls. CD4+SLAMF7+ TEM cells (but not TEMRA cells) were significantly increased among IgG4-RD patients. Within CD4+SLAMF7+ TEM cells, CD8?- cells but not CD8?low cells were elevated in IgG4-RD patients. The same dominant clones of CD8?-CD4+SLAMF7+ TEM cells found in peripheral blood were also identified in affected tissue. CD8?- and CD8?low CD4+SLAMF7+ TEM cells both expressed cytolytic molecules. Clonally expanded CD8?- but not CD8?low CD4+SLAMF7+ TEM cells decreased following glucocorticoid-induced disease remission. CONCLUSION:A subset of CD8?-CD4+SLAMF7+ cytotoxic TEM cells is oligoclonally expanded in patients with active IgG4-RD. This TEM cell population contracts following glucocorticoid-induced remission. Further characterization of this cell population may provide prognostic information and targets for therapeutic intervention.

Project description:OBJECTIVE:To determine the number and function of follicular helper T (Tfh) cell subsets in IgG4-related disease (IgG4-RD). METHODS:Mononuclear cells from the peripheral blood and involved tissue of patients with IgG4-RD were assessed for Tfh cells and their subsets, and levels of B cell lymphoma 6 (Bcl-6), B lymphocyte-induced maturation protein 1 (BLIMP-1), and interleukin-21 (IL-21) messenger RNA (mRNA). Immunohistochemical and immunofluorescence techniques were used to assess the involved tissue of patients to determine the location of IL-21, Bcl-6, and CD4+CXCR5+ Tfh cells. Furthermore, the ability of circulating Tfh (cTfh) cell subsets to induce B cell proliferation, apoptosis, and differentiation and to produce IgG4 was explored in cell cocultures in vitro. RESULTS:Frequencies of cTfh cells were significantly increased in the peripheral blood of patients with IgG4-RD, and even higher frequencies were observed in the involved tissue. Percentages of programmed cell death protein 1 in CD4+CXCR5+ICOS+ cTfh cells were positively correlated with the serum levels of IgG and IgG4, IgG4:IgG ratio, number of involved organs, and frequency of CD19+CD24-CD38high plasmablasts/plasma cells. Levels of BLIMP-1 and IL-21 mRNA in peripheral CD4+ T cells were increased in patients with IgG4-RD compared to healthy controls, and this was correlated with the levels of serum IgG4. Moreover, in the involved tissue, Bcl-6, IL-21, and Tfh cells were highly expressed. Compared to cTfh cells from healthy controls, cTfh cells from patients with IgG4-RD could facilitate B cell proliferation and inhibit B cell apoptosis more efficiently, and enhanced the differentiation of naive B cells into switched memory B cells and plasmablasts/plasma cells, with a resultant increase in the secretion of IgG4. Notably, the cTfh1 and cTfh2 cell subsets were the most effective at providing B cell help. CONCLUSION:Tfh cell subsets are expanded in IgG4-RD and may play pivotal roles in the pathogenesis of the disease.

Dataset Information

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

Publications

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

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