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

Abstract

Background IgG4-related disease (IgG4-RD) is a systemic condition of unknown etiology, 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 IgG4-RD subjects based on their clonal expansion and their ability to infiltrate affected tissue sites. Methods We used flow cytometry to identify CD4+ effector/memory T cells (TEM) in a cohort of 101 IgG4-related disease (IgG4-RD) patients. These expanded cells were characterized by gene expression analysis and flow cytometry. Next-generation sequencing of the T cell receptor β chain gene was performed on CD4+SLAMF7+ CTLs and CD4+GATA3+ TH2 cells in a subset of patients to identify their clonality. Tissue infiltration by specific T cells was examined using quantitative multi-color imaging. Results CD4+ effector/memory T cells with a cytolytic phenotype were expanded in IgG4-RD patients. Next-generation sequencing revealed prominent clonal expansions of these CD4+CTLs but not CD4+GATA3+ memory TH2 cells in subjects 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 disease-associated CD4+ CTLs Conclusions IgG4-RD is prominently linked to clonally-expanded, IL-1β, and TGF- β1 secreting, CD4+ CTLs in peripheral blood as well as in 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.

Emerging Treatment Models in Rheumatology: IgG4‐Related Disease: Insights Into Human Immunology and Targeted Therapies

“…42 Subsequent studies analyzing the T cell repertoire from subjects with active IgG4-RD who also had a history of atopy documented no clonal expansions of Th2 cells but rather indicated diverse polyclonality, consistent with a lifetime of exposure to environmental allergens. 43 In contrast, the same study detected a highly-restricted repertoire in a separate T-cell population: cytotoxic CD4 + T-cells (CD4 + CTLs). 43 …”

Neurological Manifestations of IgG4-Related Disease

“…Indeed, the effectiveness of B cell depletion therapy in IgG4-RD suggests that B lymphocytes and other cells of this lineage play an important pathological role, probably via their interaction with CD4 + cytotoxic T lymphocytes (CTL) serving as effective antigen-presenting cells and/or through the secretion of B cell-derived growth factors [42, 43]. …”

“…The recent characterisation of a clonally expanded population of CD4 + CTL in both the peripheral blood and fibrotic lesions of IgG4-RD patients suggests that these cells are indeed central to the disease pathogenesis [41, 43, 49]. Mattoo et al demonstrated that CD4 + CTL cells which also expressed signalling lymphocytic activation molecule F7 (SLAMF7) were expanded in patients with IgG4-RD, and these cells expressed granzyme B, perforin, IL-1β, TGF-β and IFN-γ, which may be important mediators of tissue damage [43]. Rituximab-induced clinical remission was associated with a reduction in the number of these CD4 + CTL, but had minimal or no effect on the frequency and number of CD4 + GATA3 + Th2 phenotype cells or CD4 + CD25 + Foxp3 + regulatory T cells [49].…”

IgG4-Related Disease Presenting as Isolated Scleritis

“…The clonally expanded population of CD4+ cytotoxic T lymphocytes in both the peripheral blood and the fibrotic lesions of IgG4-RD patients suggests that these cells are central to the disease. Mattoo et al [7] reported that IL-1, TGF-beta, and interferon-gamma expressed by these cells are all potentially important mediators of the fibrosis which is a dominant part of the histopathology in IgG4-RD [7]. In the same work, the authors demonstrated that the number of these cells decreased concomitantly with a clinical response to rituximab therapy, suggesting a contributory role for these CD4+ cytotoxic T cells in the pathogenesis of IgG4-RD.…”