Chemokine receptor expression and function in CD4+ T lymphocytes with regulatory activity.
We have investigated the chemokine receptor expression and migratory behavior of a new subset of nickel-specific skin-homing regulatory CD4(+) T cells (Th(IL-10)) releasing high levels of IL-10, low IFN-gamma, and undetectable IL-4. These cells inhibit in a IL-10-dependent manner the capacity of dendritic cells to activate nickel-specific Tc1 and Th1 lymphocytes. RNase protection assay and FACS analysis revealed the expression of a vast repertoire of chemokine receptors on resting Th(IL-10), including the Th1-associated CXCR3 and CCR5, and the Th2-associated CCR3, CCR4, and CCR8, the latter at higher levels compared with Th2 cells. The most active chemokines for resting Th(IL-10), in terms of calcium mobilization and in vitro migration, were in order of potency: CCL2 (monocyte chemoattractant protein-1, CCR2 ligand), CCL4 (macrophage-inflammatory protein-1beta, CCR5 ligand), CCL3 (macrophage-inflammatory protein-1alpha, CCR1/5 ligand), CCL17 (thymus and activation-regulated chemokine, CCR4 ligand), CCL1 (I-309, CCR8 ligand), CXCL12 (stromal-derived factor-1, CXCR4), and CCL11 (eotaxin, CCR3 ligand). Consistent with receptor expression down-regulation, activated Th(IL-10) exhibited a reduced or absent response to most chemokines, but retained a significant migratory capacity to I-309, monocyte chemoattractant protein-1, and thymus and activation-regulated chemokine. I-309, which was ineffective on Th1 lymphocytes, attracted more efficiently Th(IL-10) than Th2 cells. I-309 and CCR8 mRNAs were not detected in unaffected skin and were up-regulated at the skin site of nickel-allergic reaction, with an earlier expression kinetics compared with IL-10 and IL-4. Results indicate that skin-homing regulatory Th(IL-10) lymphocytes coexpress functional Th1- and Th2-associated chemokine receptors, and that CCR8/I-309-driven recruitment of both resting and activated Th(IL-10) cells may be critically involved in the regulation of Th1-mediated skin allergic disorders.
Sebastiani
S
S
Laboratory of Immunology, Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy.
Allavena
P
P
Albanesi
C
C
Nasorri
F
F
Bianchi
G
G
Traidl
C
C
Sozzani
S
S
Girolomoni
G
G
Cavani
A
A
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002460:Cell Line; D054402:Chemokine CCL1; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D017449:Dermatitis, Allergic Contact / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D007399:Interphase / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D009532:Nickel / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D054401:Receptors, CCR8; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
C065971:CCL1 protein, human; C103330:CCR8 protein, human; D054402:Chemokine CCL1; D019742:Chemokines, CC; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D012333:RNA, Messenger; D054401:Receptors, CCR8; D019707:Receptors, Chemokine; D016753:Interleukin-10; D009532:Nickel