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

Background: IgG(4)-related disease (IgG(4)-RD) is a systemic condition of unknowncause characterized by highly fibrotic lesions with dense lymphoplasmacytic infiltrates. CD4(+) T cells constitute the major inflammatory cell population in IgG(4)-RD lesions. Objective: We used an unbiased approach to characterize CD4(+) T-cell subsets in patients with IgG(4)-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 IgG(4)-RD. These expanded cells were characterized by means of gene expression analysis and flow cytometry. Next-generation sequencing of the T-cell receptor beta chain gene was performed on CD4(+) SLAMF7(+) cytotoxic T lymphocytes (CTLs) and CD4(+) GATA3(+) T(H)2 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 dominantTcells infiltrating a range of inflamed IgG(4)-RD tissue sites were clonally expanded CD4(+) CTLs that expressed SLAMF7, granzyme A, IL-1 beta, and TGF-beta 1. Clinical remission induced by rituximab-mediated B-cell depletion was associated with a reduction in numbers of disease-associated CD4(+) CTLs. Conclusions: IgG(4)-RD is prominently linked to clonally expanded IL-1 beta- and TGF-beta 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.