Dataset Information

Skin-Resident Effector Memory CD8+CD28- T Cells Exhibit a Profibrotic Phenotype in Patients with Systemic Sclerosis.

ABSTRACT: Loss of CD28 expression by CD8+ T cells occurs with age and during chronic inflammatory conditions. CD8+CD28- T cells are a heterogeneous cell subpopulation whose function ranges from immunosuppressive to effector. Here we analyzed the role of CD8+CD28- T cells in the pathogenesis of systemic sclerosis (SSc), a connective tissue disorder characterized by autoimmunity, vasculopathy, and extensive cutaneous and visceral fibrosis. We show that the frequency of CD8+CD28- T cells is increased in the blood and affected skin of SSc patients, independent of patient age, and correlates with the extent of skin fibrosis. We found that most skin-tropic CD8+CD28- T cells are resident in the skin lesions of patients in the early stage of the disease, exhibit an effector memory phenotype, and present a strong cytolytic activity ex vivo. Skin-resident and circulating SSc CD8+CD28- T cells produce high levels of the profibrotic cytokine IL-13, which induces collagen production by normal and SSc dermal fibroblasts. Thus, our findings indicate that CD8+CD28- T cells represent a pathogenic T-cell subset in SSc and likely play a critical role in the early stage of SSc skin disease.

SUBMITTER: Li G

PROVIDER: S-EPMC5433864 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Skin-Resident Effector Memory CD8+CD28- T Cells Exhibit a Profibrotic Phenotype in Patients with Systemic Sclerosis.

Li Gang G Larregina Adriana T AT Domsic Robyn T RT Stolz Donna B DB Medsger Thomas A TA Lafyatis Robert R Fuschiotti Patrizia P

The Journal of investigative dermatology 20161222 5

Loss of CD28 expression by CD8+ T cells occurs with age and during chronic inflammatory conditions. CD8+CD28- T cells are a heterogeneous cell subpopulation whose function ranges from immunosuppressive to effector. Here we analyzed the role of CD8+CD28- T cells in the pathogenesis of systemic sclerosis (SSc), a connective tissue disorder characterized by autoimmunity, vasculopathy, and extensive cutaneous and visceral fibrosis. We show that ...[more]

PMID: 28012718

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Project description:BackgroundSystemic sclerosis (SSc) is an autoimmune disease characterized by overproduction of extracellular matrix (ECM) and multiorgan fibrosis. Animal studies pointed to bone marrow-derived cells as a potential source of pathological ECM-producing cells in immunofibrotic disorders. So far, involvement of monocytes and macrophages in the fibrogenesis of SSc remains poorly understood.Methods and resultsImmunohistochemistry analysis showed accumulation of CD14+ monocytes in the collagen-rich areas, as well as increased amount of alpha smooth muscle actin (αSMA)-positive fibroblasts, CD68+ and mannose-R+ macrophages in the heart and lungs of SSc patients. The full genome transcriptomics analyses of CD14+ blood monocytes revealed dysregulation in cytoskeleton rearrangement, ECM remodeling, including elevated FN1 (gene encoding fibronectin) expression and TGF-β signalling pathway in SSc patients. In addition, single cell RNA sequencing analysis of tissue-resident CD14+ pulmonary macrophages demonstrated activated profibrotic signature with the elevated FN1 expression in SSc patients with interstitial lung disease. Peripheral blood CD14+ monocytes obtained from either healthy subjects or SSc patients exposed to profibrotic treatment with profibrotic cytokines TGF-β, IL-4, IL-10, and IL-13 increased production of type I collagen, fibronectin, and αSMA. In addition, CD14+ monocytes co-cultured with dermal fibroblasts obtained from SSc patients or healthy individuals acquired a spindle shape and further enhanced production of profibrotic markers. Pharmacological blockade of the TGF-β signalling pathway with SD208 (TGF-β receptor type I inhibitor), SIS3 (Smad3 inhibitor) or (5Z)-7-oxozeaenol (TGF-β-activated kinase 1 inhibitor) ameliorated fibronectin levels and type I collagen secretion.ConclusionsOur findings identified activated profibrotic signature with elevated production of profibrotic fibronectin in CD14+ monocytes and CD14+ pulmonary macrophages in SSc and highlighted the capability of CD14+ monocytes to acquire a profibrotic phenotype. Taking together, tissue-infiltrating CD14+ monocytes/macrophages can be considered as ECM producers in SSc pathogenesis.

Dataset Information

Skin-Resident Effector Memory CD8+CD28- T Cells Exhibit a Profibrotic Phenotype in Patients with Systemic Sclerosis.

Publications

Skin-Resident Effector Memory CD8<sup>+</sup>CD28<sup>-</sup> T Cells Exhibit a Profibrotic Phenotype in Patients with Systemic Sclerosis.

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