Occurrence of an activated, profibrotic pattern of gene expression in lung CD8+ T cells from scleroderma patients

Luzina, Irina G.; Atamas, Sergei P.; Wise, Robert A.; Wigley, Fredrick M.; Choi, Jung Min; Xiao, Hui; White, Barbara

doi:10.1002/art.11080

Cited by 108 publications

(108 citation statements)

References 84 publications

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“…By allowing a direct comparison of IFN␥ and IL-4 production potential between T cell subsets generated from healthy and SSc skin, our data highlight the point that CD4ϩCD8ϩ DP as well as CD8ϩ SP T cells, rather than CD4ϩ SP T cells, are the cells producing the high amounts of IL-4. Our results are reminiscent of the finding that the presence of CD8ϩ T cells producing IL-4 in the bronchoalveolar lavage fluid of patients with SSc correlates with development of lung fibrosis (40,41). DP T cells have been observed in patients with various pathologic conditions as well as in normal donors (1).…”

Section: Discussionsupporting

confidence: 69%

Presence of CD4+CD8+ double‐positive T cells with very high interleukin‐4 production potential in lesional skin of patients with systemic sclerosis

Parel¹,

Aurrand-Lions²,

Scheja³

et al. 2007

Arthritis & Rheumatism

129

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Objective. Fibrotic skin changes in systemic sclerosis (SSc) are preceded by the appearance of an inflammatory infiltrate rich in T cells. Since no direct comparison with T cells in normal skin has been performed previously, this study was undertaken to functionally characterize T cells in the skin of patients with early active SSc and in normal skin.Methods. We characterized coreceptor expression, T cell receptor (TCR) usage, cytokine production, and helper and cytolytic activity of T cell lines and clones established from skin biopsy specimens from 6 SSc patients and 4 healthy individuals. Immunofluorescence analysis of skin biopsy and peripheral blood samples was performed to confirm the presence of specific subsets in vivo.Results. A distinct subset expressing both CD4 and CD8␣/␤ coreceptors at high levels (double-positive [DP]) was present in T cell lines from SSc and normal skin. DP T cells actively transcribed both accessory molecules, exerted clonally distributed cytolytic and helper activity, and expressed TCR clonotypes distinct from those in CD4؉ or CD8؉ single-positive (SP) T cells. In SSc skin, DP T cells produced very high levels of interleukin-4 (IL-4) compared with CD4؉ SP T cells. Furthermore, DP T cells were directly identified in SSc skin, thus providing evidence that they are a distinct subset in vivo.Conclusion. The present findings show that T cells with the unusual CD4؉CD8؉ DP phenotype are present in the skin. Their very high level of IL-4 production in early active SSc may contribute to enhanced extracellular matrix deposition by fibroblasts.

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Section: Discussionsupporting

confidence: 69%

Presence of CD4+CD8+ double‐positive T cells with very high interleukin‐4 production potential in lesional skin of patients with systemic sclerosis

Parel¹,

Aurrand-Lions²,

Scheja³

et al. 2007

Arthritis & Rheumatism

129

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“…Previous studies have reported that CD8 + T cells infiltrated the skin (6) and lung (7,8) in SSc patients and that CD8 + T cells in lung and peripheral blood showed an activated phenotype (7,9) and Agdriven oligoclonal expansion (8,10,11). These findings indicate that effector or memory CD8 + T cells, or both, are involved in SSc pathogenesis.…”

mentioning

confidence: 68%

“…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).…”

Section: Patientsmentioning

confidence: 99%

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

Ayano

Tsukamoto

Kohno

et al. 2015

The Journal of Immunology

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Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular damage and fibrosis of the skin and internal organs. Because activated and oligoclonally expanded CD8+ T cells can be detected in peripheral blood and lungs of SSc patients, effector memory CD8+ T cells may play a critical role for organ involvement in SSc; however, the pathogenic functions of effector memory CD8+ T cells remain incompletely understood. In this study, we performed DNA microarray analysis of the sort-purified effector memory CD8+ T cells from SSc patients and healthy controls, and showed that the expression of genes related to immune response and cell adhesion, including CD226 (also known as DNAX accessory molecule-1 [DNAM-1]), was significantly altered. Moreover, detailed analysis of CD226 revealed that CD226highCD8+ T cells were increased in SSc patients (mean, 50.7%) compared with healthy controls (32.9%) and were appreciably associated with the severity of skin sclerosis and interstitial lung disease. Furthermore, CD226+CD8+ T cells produced higher amount of various cytokines than CD226− ones, and CD226highCD8+ T cells from SSc patients showed upregulated IL-13 production and positive correlation with the cytotoxic capacity of CD8+ T cells against HUVECs. Finally, the neutralization of CD226 in CD8+ T cells impaired costimulation, cytokine productions, and cytolysis against HUVECs. These findings indicate that upregulated CD226 expression on CD8+ T cells reflects disease severity and is involved in SSc pathogenesis via the production of various cytokines, including profibrotic IL-13 and endothelial cell injury, and that CD226 may be a useful target in the treatment of SSc.

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“…CD8ϩ T cells are seen in the pulmonary interstitium on lung biopsy specimens and are increased in the bronchoalveolar lavage fluid from SSc patients with active lung disease (alveolitis) compared with SSc patients with inactive lung disease or no lung disease (11). These T cells exhibit an activated phenotype (HLA-DRϩ), and their presence in the bronchoalveolar lavage fluid is quantitatively associated with progressive and more severe ILD (12,13). Similarly, activated T cells are described in skin biopsy specimens from SSc patients who have early active cutaneous involvement (14).…”

mentioning

confidence: 99%

“…Th2 cytokine expression and secretion are increased in T cells isolated from newly affected SSc skin (21,22). Activated CD8ϩ T cells in bronchoalveolar lavage fluid from SSc patients with alveolitis have higher type 2 cytokine (IL-4 and IL-5) messenger RNA (mRNA) expression (12,13). These data suggest that in SSc, a specific population of activated T cells exhibiting a profibrotic Th2/Tc2-polarized phenotype may be potentially relevant in mediating tissue fibrosis.…”

mentioning

confidence: 99%

T cell polarization identifies distinct clinical phenotypes in scleroderma lung disease

Boin¹,

Fanis²,

Bartlett³

et al. 2008

Arthritis & Rheumatism

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Objective. Lung involvement is the leading cause of morbidity and mortality in systemic sclerosis (SSc; scleroderma), and interstitial lung disease (ILD) is the most common pulmonary manifestation. An abnormal profibrotic Th2/Tc2-polarized T cell response is postulated to mediate tissue damage and fibrosis. The aim of this study was to investigate whether a polarized T cell phenotype in SSc is associated with lung disease or other clinical manifestations of SSc.Methods. Circulating T cells were characterized by flow cytometry in 62 patients with SSc and 36 healthy control subjects, using antibodies against CD3, CD4, CD8, chemokine receptor CCR5 (Th1/Tc1-specific), and prostaglandin D 2 receptor CRTH2 (Th2/Tc2-specific). The ratio between CCR5 and CRTH2 T cell frequencies was used to quantify type 1 (high-ratio) or type 2 (low-ratio) immune polarization.Results. Patients with SSc exhibited lower CCR5/ CRTH2 T cell ratios than those exhibited by control subjects (P < 0.0001), indicating a Th2/Tc2-polarized phenotype. Markedly reduced CCR5/CRTH2 T cell ratios were observed in SSc patients with ILD compared with SSc patients without ILD (P < 0.0001), particularly in patients with active ILD (P < 0.0001) compared with those with stable lung function. Lower CCR5/ CRTH2 ratios were strongly associated with a lower value for the percent predicted forced vital capacity (P < 0.0001). In patients with an estimated right ventricular systolic pressure >35 mm Hg, suggestive of pulmonary vascular disease, a lower value for the percent predicted diffusing capacity (DLCO) was associated with higher CCR5/CRTH2 T cell ratios (Th1/Tc1) (P ‫؍‬ 0.009), while in those with right ventricular systolic pressure <35 mm Hg, a lower value for the percent predicted DLCO correlated with lower ratios (Th2/Tc2) (P < 0.0001), as observed for ILD.

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Occurrence of an activated, profibrotic pattern of gene expression in lung CD8+ T cells from scleroderma patients

Cited by 108 publications

References 84 publications

Presence of CD4+CD8+ double‐positive T cells with very high interleukin‐4 production potential in lesional skin of patients with systemic sclerosis

Presence of CD4+CD8+ double‐positive T cells with very high interleukin‐4 production potential in lesional skin of patients with systemic sclerosis

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

T cell polarization identifies distinct clinical phenotypes in scleroderma lung disease

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