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Role for CXCR6 and Its Ligand CXCL16 in the Pathogenesis of T-Cell Alveolitis in Sarcoidosis

Departments of Clinical and Experimental Medicine, Clinical Immunology and Hematology Branches, Division of Pneumology and Institute of Pathology, Padua University School of Medicine, Padua, Italy

Correspondence and requests for reprints should be addressed to Carlo Agostini, M.D., Dipartimento di Medicina Clinica e Sperimentale, Università di Padova, Immunologia Clinica and Ematologia, Via Giustiniani 2, 35128 Padova, Italy. E-mail: carlo.agostini{at}unipd.it

Rationale: Receptor expression dictates the spectrum of chemokine actions on immunocompetent cells. We have previously shown that the chemokine receptor CXCR3 is highly expressed by T-helper type 1 (Th1) cells infiltrating the lungs 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 bronchoalveolar lavage 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, although CXCR3 was rapidly induced by interleukin (IL)-15 and IL-18, CXCR6 induction was slow (8 d) 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: chemokines • granuloma • immunopathogenesis • sarcoidosis • T-cell alveolitis

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