Human CD25+ regulatory T cells maintain immune tolerance to nickel in healthy, nonallergic individuals.
We investigated the capacity of CD25(+) T regulatory cells (Treg) to modulate T cell responses to nickel, a common cause of allergic contact dermatitis. CD4(+) T cells isolated from the peripheral blood of six healthy, nonallergic individuals showed a limited capacity to proliferate in response to nickel in vitro, but responsiveness was strongly augmented (mean increment +/- SD, 240 +/- 60%) when cells were depleted of CD25(+) Treg. Although CD25(+) Treg were anergic to nickel, a small percentage up-regulated membrane CTLA-4 upon nickel exposure. CD25(+) Treg strongly and dose-dependently inhibited nickel-specific activation of CD25(-) T lymphocytes in coculture experiments in a cytokine-independent, but cell-to-cell contact-dependent, manner. Approximately 30% of circulating CD25(+) Treg expressed the cutaneous lymphocyte-associated Ag (CLA), and CLA(+)CD25(+) Treg were more efficient than CLA(-)CD25(+) cells in suppressing nickel responsiveness of CD25(-) T cells. The site of a negative patch test in response to nickel showed an infiltrate of CD4(+)CLA(+) cells and CD25(+) cells, which accounted for approximately 20% of the total T cells isolated from the tissue. Skin-derived T cells suppressed nickel-specific responses of peripheral blood CD25(-) T cells. In addition, 60 +/- 14% of peripheral blood CD25(+) Treg expressed the chemokine receptor CCR7 and strongly inhibited naive T cell activation in response to nickel. Finally, CD25(+) T cells isolated from peripheral blood of nickel-allergic patients showed a limited or absent capacity to suppress metal-specific CD4(+) and CD8(+) T cell responses. The results indicates that in healthy individuals CD25(+) Treg can control the activation of both naive and effector nickel-specific T cells.
Cavani
Andrea
A
Laboratory of Immunology, Istituto Dermopatico dell'Immacolata, Rome, Italy. cavani@idi.it
Nasorri
Francesca
F
Ottaviani
Chiara
C
Sebastiani
Silvia
S
De Pità
Ornella
O
Girolomoni
Giampiero
G
D000328:Adult; D000485:Allergens / Q000097:blood / Q000276:immunology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen; D002450:Cell Communication / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002469:Cell Separation; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology; D016207:Cytokines / Q000502:physiology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D017449:Dermatitis, Allergic Contact / Q000097:blood / Q000276:immunology / Q000473:pathology; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D006241:Haptens / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D009532:Nickel / Q000097:blood / Q000276:immunology*; D010328:Patch Tests; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis* / Q000097:blood; D012867:Skin / Q000166:cytology / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000276:immunology
D000485:Allergens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; C515370:CCR7 protein, human; C063419:CTAGE1 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; D006241:Haptens; D008562:Membrane Glycoproteins; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D015375:Receptors, Interleukin-2; D009532:Nickel