Role for CXCR6 and its ligand CXCL16 in the pathogenesis of T-cell alveolitis in sarcoidosis.
BACKGROUND
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.


OBJECTIVE
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.


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.
Agostini
Carlo
C
Department of Clinical Medicine, Clinical Immunology Branch, Division of Pneumology and Institute of Pathology, Padua University School of Medicine, Italy. carlo.agostini@unipd.it
Cabrelle
Anna
A
Calabrese
Fiorella
F
Bortoli
Michela
M
Scquizzato
Elisa
E
Carraro
Samuela
S
Miorin
Marta
M
Beghè
Bianca
B
Trentin
Livio
L
Zambello
Renato
R
Facco
Monica
M
Semenzato
Gianpietro
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018893:Bronchoalveolar Lavage; D002465:Cell Movement / Q000502:physiology; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC / Q000502:physiology*; D002908:Chronic Disease; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000502:physiology*; D051116:Receptors, Scavenger / Q000502:physiology*; D011991:Receptors, Virus / Q000502:physiology*; D017565:Sarcoidosis, Pulmonary / Q000503:physiopathology*; D013601:T-Lymphocytes / Q000378:metabolism*; D018417:Th1 Cells / Q000502:physiology
C423727:CXCL16 protein, human; C106330:CXCR6 protein, human; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D051116:Receptors, Scavenger; D011991:Receptors, Virus