CCL22-induced responses are powerfully enhanced by synergy inducing chemokines via CCR4: evidence for the involvement of first beta-strand of chemokine.
In an attempt to clarify how cells integrate the signals provided by multiple chemokines expressed during inflammation, we have uncovered a novel mechanism regulating leukocyte trafficking. Our data indicate that the concomitant exposure to CCR4 agonists and CXCL10/IP-10 strongly enhances the chemotactic response of human T lymphocytes. This enhancement is synergistic rather than additive and occurs via CCR4 since it persists after CXCR3 blockade. Besides chemotaxis, other cellular responses are enhanced upon stimulation of CCR4-transfected cells with CCL22/MDC plus CXCL10. Several other chemokines in addition to CXCL10 were able to increase CCL22-mediated chemotaxis. The first beta-strand of the chemokine structure is highly and specifically implicated in this phenomenon, as established using synergy-inducing and non-synergy-inducing chimeric chemokines. As shown in situ for skin from atopic and allergic contact dermatitis patients, this organ becomes the ideal environment in which skin-homing CCR4(+) T lymphocytes can accumulate under the stimulus offered by CCR4 agonists, together with the synergistic chemokines that are concomitantly expressed. Overall, our results indicate that chemokine-induced synergism strengthens leukocyte recruitment towards tissues co-expressing several chemokines.
Sebastiani
Silvia
S
Institute for Research in Biomedicine, Bellinzona, Switzerland.
Danelon
Gabriela
G
Gerber
Basil
B
Uguccioni
Mariagrazia
M
D000595:Amino Acid Sequence; D002460:Cell Line; D054422:Chemokine CCL22; D054357:Chemokine CXCL10; D018925:Chemokines / Q000737:chemistry* / Q000276:immunology; D019742:Chemokines, CC / Q000276:immunology*; D019743:Chemokines, CXC / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D017449:Dermatitis, Allergic Contact / Q000276:immunology; D003876:Dermatitis, Atopic / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008969:Molecular Sequence Data; D009924:Organ Culture Techniques; D017433:Protein Structure, Secondary; D054398:Receptors, CCR4; D019707:Receptors, Chemokine / Q000276:immunology*; D012867:Skin / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
C515482:CCL22 protein, human; C515354:CCR4 protein, human; D054422:Chemokine CCL22; D054357:Chemokine CXCL10; D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; D054398:Receptors, CCR4; D019707:Receptors, Chemokine