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 b 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 1b, and TGF b1. 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 1b and TGF b1 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.
The Journal of allergy and clinical immunology