Evidence for functional relevance of CTLA-4 in ultraviolet-radiation-induced tolerance.
Hapten sensitization through UV-exposed skin induces hapten-specific tolerance that can be adoptively transferred by injecting T lymphocytes into naive recipients. The exact phenotype of T cells responsible for inhibiting the immune response and their mode of action remain unclear. Evidence exists that CTLA-4 negatively regulates T cell activation. We addressed whether CTLA-4 is involved in the transfer of UV-induced tolerance. Injection of lymph node cells from mice that were sensitized with dinitrofluorobenzene (DNFB) through UV-irradiated skin inhibited induction of contact hypersensitivity against DNFB in the recipient animals. When CTLA-4+ cells were depleted, transfer of suppression was lost. Likewise, significantly fewer lymphocytes enriched for CTLA-4+ cells were necessary to transfer suppression than unfractionated cells. Expression of CTLA-4 appears to be functionally relevant, since in vivo injection of a blocking anti-CTLA-4 Ab was able to break UV-induced tolerance and inhibited transfer of suppression. Upon stimulation with dendritic cells in the presence of the water-soluble DNFB analogue, DNBS, CTLA-4+ T cells from DNFB-tolerized mice secreted high levels of IL-10, TGF-beta, and IFN-gamma; low levels of IL-2; and no IL-4, resembling the cytokine pattern of T regulatory 1 cells. Ab blocking of CTLA-4 resulted in inhibition of IL-10 release. Accordingly, transfer of tolerance was not observed when recipients were treated with an anti-IL-10 Ab. Hence we propose that T cells, possibly of the T regulatory 1 type, transfer UV-mediated suppression through the release of IL-10. Activation of CTLA-4 appears to be important in this process.
Schwarz
A
A
Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin, Department of Dermatology, University of Münster, Münster, Germany.
Beissert
S
S
Grosse-Heitmeyer
K
K
Gunzer
M
M
Bluestone
J A
JA
Grabbe
S
S
Schwarz
T
T
D000069594:Abatacept; D019264:Adoptive Transfer; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology* / Q000528:radiation effects; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D007108:Immune Tolerance / Q000528:radiation effects*; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000276:immunology / Q000528:radiation effects; D007274:Injections, Intraperitoneal; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008212:Lymphocyte Depletion; D017710:Lymphocyte Transfusion; D051379:Mice; D008809:Mice, Inbred C3H; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects; D014466:Ultraviolet Rays
D019138:Antibodies, Blocking; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D016753:Interleukin-10; D000069594:Abatacept