Effector CD8+ T cells in systemic sclerosis patients produce abnormally high levels of interleukin‐13 associated with increased skin fibrosis

Abstract

Objective. T lymphocytes play an important role in systemic sclerosis (SSc), a connective tissue disease characterized by inflammation, fibrosis, and vascular damage. While their precise role and antigen specificity are unclear, T cell-derived cytokines likely contribute to the induction of fibrosis. The aim of this study was to establish the role of cytokine dysregulation by T cells in the pathogenesis of SSc.Methods. To identify relationships between a specific cytokine, T cell subset, and the disease course, we studied a large cohort of patients with diffuse cutaneous SSc (dcSSc) or limited cutaneous SSc (lcSSc). Using Luminex analysis and intracellular cytokine staining, we analyzed the intrinsic ability of CD4؉ and CD8؉ T cell subsets to produce cytokines following in vitro activation.Results. High levels of the profibrotic type 2 cytokine interleukin-13 (IL-13) were produced following activation of peripheral blood effector CD8؉ T cells from SSc patients as compared with normal controls or with patients with rheumatoid arthritis. In contrast, CD4؉ T cells showed a lower and more variable level of IL-13 production. This abnormality correlated with the extent of fibrosis and was more pronounced in dcSSc patients than in lcSSc patients. Conclusion. Dysregulated IL-13 production by effector CD8؉ T cells is important in the pathogenesis of SSc and is critical in the predisposition to more severe forms of cutaneous disease. Our study is the first to identify a specific T cell phenotype that correlates with disease severity in SSc and can be used as a marker of immune dysfunction in SSc and as a novel therapeutic target.

Increased CD226 Expression on CD8+ T Cells Is Associated with Upregulated Cytokine Production and Endothelial Cell Injury in Patients with Systemic Sclerosis

“…The disease duration was calculated from the time of onset of the first non-Raynaud phenomenon. Skin sclerosis was evaluated with the modified Rodnan skin thickness score (MRSS) (19) and graded as mild (MRSS, [1][2][3][4][5][6][7][8][9][10][11][12][13][14] or moderateto-severe (MRSS, 15-39) (20). SSc-related interstitial lung disease (ILD) was classified as extensive or limited disease based on combined evaluation with chest high-resolution computed tomography (HRCT) and pulmonary functional tests (21).…”

“…These findings indicate that effector or memory CD8 + T cells, or both, are involved in SSc pathogenesis. Recent reports have shown that effector CD8 + T cells were directly involved in modulating dermal fibrosis in SSc via dysregulated IL-13 production (6,12). Memory T cells contain two populations of central memory and effector memory cells characterized by distinct homing potentials and effector functions (13).…”

Interleukin-13 is overexpressed in cutaneous T-cell lymphoma cells and regulates their proliferation

“…IL-13 plays a critical role in pathologic processes such as asthma, 20 fibrosis, 21,22 and cancer. 21,23 Several studies implicate IL-13 as an autocrine factor for several tumors that express IL-13Ra1, the signaling receptor for IL-13, 24 including Hodgkin lymphoma, 25,26 B-CLL, 27 and breast carcinoma.…”

Biological Therapy in Systemic Sclerosis

“…There was a dysregulation in IL-13 production by effector CD8+ T-cells in SSc, not present in the healthy control group or in rheumatoid arthritis patients (p < 0.001). This dysregulated IL-13 production also correlated with the extent of skin fibrosis, with dcSSc showing higher levels of IL-13 compared with lcSSc (p < 0.01) [33].…”