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

详细信息    查看全文

• 作者：Hamid Mattoo ; PhD^a ; ^&lowast ; ; Vinay S. Mahajan ; MBBS ; PhD^a ; ^&lowast ; ; Takashi Maehara ; DDS ; PhD^a ; ^b ; Vikram Deshpande ; MD^a ; Emanuel Della-Torre ; MD^a ; Zachary S. Wallace ; MD^a ; Maria Kulikova ; BS^a ; Jefte M. Drijvers ; MD^a ; Joe Daccache ; BS^a ; Mollie N. Carruthers ; MD^a ; Flavia V. Castelino ; MD^a ; James R. Stone ; MD ; PhD^a ; John H. Stone ; MD ; MPH^a ; ^{jhstone@partners.org" class="auth_mail" title="E-mail the corresponding author} ; Shiv Pillai ; MBBS ; PhD^a ; ^{pillai@helix.mgh.harvard.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Fibrosis ; IgG4-related disease ; IgG4 ; CD4+ cytotoxic T cells ; TH2 cells ; rituximab ; IL-1β
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：138
• 期：3
• 页码：825-838
• 全文大小：3583 K

文摘

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⁺ T_H2 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 T_H2 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.