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

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⁺ 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.