Published ahead of print on August 11, 2005, doi:10.1164/rccm.200501-142OC
Am. J. Respir. Crit. Care Med., Volume 172, Number 10, November 2005, 1290-1298
A more recent version of this article appeared on November 15, 2005
Submitted on January 28, 2005
Accepted on August 5, 2005
Role for CXCR6 and its Ligand CXCL16 in the Pathogenesis of T-cell Alveolitis in Sarcoidosis
Carlo Agostini1*, Anna Cabrelle1, Fiorella Calabrese2, Michela Bortoli1, Elisa Scquizzato1, Samuela Carraro1, Marta Miorin1, Bianca Beghe3, Livio Trentin1, Renato Zambello1, Monica Facco1, and Gianpietro Semenzato1
1 Departments of Clinical and Experimental Medicine, Clinical Immunology and Hematology Branches, Padua University School of Medicine, Padua, Italy,
2 Department of Pathology, Padua University School of Medicine, Padua, Italy,
3 Department of Pneumology, Padua University School of Medicine, Padua, Italy
* To whom correspondence should be addressed. E-mail: carlo.agostini{at}unipd.it.
Rationale: Receptor expression dictates the spectrum of chemokines actions on immunocompetent cells. We have previously shown that the chemokine receptor CXCR3 is
highly expressed by Th1 cells infiltrating the lung of patients with sarcoidosis.
Objectives: The evaluation of the role of Bonzo/CXCR6 and its ligand CXCL16 in the pathogenesis of sarcoidosis.
Methods: Immunocompetent cells infiltrating sarcoid lung have been evaluated by flow cytometry, confocal microscopy, immunohistochemical and molecular analysis and functional assays
Main Results: Th1 cells isolated from the BAL of patients with sarcoidosis and T-cell alveolitis coexpressed CXCR3 and CXCR6. Immunohistochemical analysis of lung specimens has shown that CXCR6(+) T cells infiltrated lung interstitium surrounding the central core of the granuloma.
The CXCR6-ligand CXCL16 was abundantly expressed by macrophages infiltrating sarcoid tissue and/or forming the granuloma core. From a functional point of view sarcoid Th1 cells were able to respond to CXCL10 and CXCL16 in migratory assay. In vitro kinetic studies demonstrated that while CXCR3 was rapidly induced by IL-15 and IL-18, CXCR6 induction was slow (8 days) and mainly regulated by IL-15.
Conclusions: T cells coexpressing CXCR3 and CXCR6 act coordinately with respective ligands and Th1 inflammatory cytokines in the alveolitic/granuloma phases of the disease.
Key words: sarcoidosis, chemokines, T-cell alveolitis, immunopathogenesis, granuloma
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