The C-C chemokine receptors CCR4 and CCR8 identify airway T cells of allergen-challenged atopic asthmatics.
In vitro polarized human Th2 cells preferentially express the chemokine receptors CCR3, CCR4, and CCR8 and migrate to their ligands: eotaxin, monocyte-derived chemokine (MDC), thymus- and activation-regulated chemokine (TARC), and I-309. We have studied the expression of chemokines and chemokine receptors in the airway mucosa of atopic asthmatics. Immunofluorescent analysis of endobronchial biopsies from six asthmatics, taken 24 hours after allergen challenge, demonstrates that virtually all T cells express IL-4 and CCR4. CCR8 is coexpressed with CCR4 on 28% of the T cells, while CCR3 is expressed on eosinophils but not on T cells. Expression of the CCR4-specific ligands MDC and TARC is strongly upregulated on airway epithelial cells upon allergen challenge, suggesting an involvement of this receptor/ligand axis in the regulation of lymphocyte recruitment into the asthmatic bronchi. In contrast to asthma, T cells infiltrating the airways of patients with chronic obstructive pulmonary disease and pulmonary sarcoidosis produce IFN-gamma and express high levels of CXCR3, while lacking CCR4 and CCR8 expression. These data support the role of CCR4, of its ligands MDC and TARC, and of CCR8 in the pathogenesis of allergen-induced late asthmatic responses and suggest that these molecules could be considered as targets for therapeutic intervention.
Panina-Bordignon
P
P
Roche Milano Ricerche, Milano, Italy. paola.panina@roche.com
Papi
A
A
Mariani
M
M
Di Lucia
P
P
Casoni
G
G
Bellettato
C
C
Buonsanti
C
C
Miotto
D
D
Mapp
C
C
Villa
A
A
Arrigoni
G
G
Fabbri
L M
LM
Sinigaglia
F
F
D001249:Asthma / Q000276:immunology*; D001706:Biopsy; D001985:Bronchial Provocation Tests; D016764:Cell Polarity; D019742:Chemokines, CC / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D008173:Lung Diseases, Obstructive / Q000276:immunology / Q000503:physiopathology; D008297:Male; D054397:Receptors, CCR3; D054398:Receptors, CCR4; D054401:Receptors, CCR8; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology*; D017565:Sarcoidosis, Pulmonary / Q000276:immunology / Q000503:physiopathology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
C515350:CCR3 protein, human; C515354:CCR4 protein, human; C103330:CCR8 protein, human; C515187:CXCR3 protein, human; D019742:Chemokines, CC; D054397:Receptors, CCR3; D054398:Receptors, CCR4; D054401:Receptors, CCR8; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D015847:Interleukin-4; D007371:Interferon-gamma