An important role of CD80/CD86-CTLA-4 signaling during photocarcinogenesis in mice.
Although previous studies have shown that altered B7 costimulation plays a critical role in UV irradiation-induced regulation of immunity, the individual roles of the B7 receptors (CD28 and CTLA-4) or the B7 family members (CD80 and CD86) have not been explored. Thus, we investigated CTLA-4 signaling during photocarcinogenesis of chronically UV-B-exposed mice using an antagonistic anti-CTLA-4 Ab. Anti-CTLA-4-treated mice developed significantly fewer UV-induced tumors. Moreover, anti-CTLA-4 treatment induced long-lasting protective immunity because progressively growing UV tumors inoculated into anti-CTLA-4- and UV-treated mice that had not developed tumors were rejected. Next, we used mice deficient for CD80, CD86, or both in photocarcinogenesis studies to assess the relative contributions of these CTLA-4 ligands. Double-deficient mice showed significantly reduced UV-induced skin tumor development, whereas CD86(-/-) mice produced skin cancer earlier compared with CD80(-/-) and control mice. The growth of UV-induced tumors appears to be controlled by UV-induced suppressor T cells, because CD80(-/-)/CD86(-/-) mice had strongly reduced numbers of UV-induced CD4(+)CD25(+) suppressor T cells. In vitro, CTLA-4 blockade inhibited the suppressor activity of UV-induced CD4(+)CD25(+) T cells, suggesting that reduced photocarcinogenesis might be due to decreased numbers or function of suppressor T cells. Together, these data indicate that blocking CD80/86-CTLA-4 signaling induced immune protection against the development of UV-induced skin tumors. Furthermore, CD86-mediated costimulation appears to play a more critical role in the protection against photocarcinogenesis than CD80.
Loser
Karin
K
Department of Dermatology, University of Munster, Munster, Germany.
Scherer
Andrea
A
Krummen
Mathias B W
MB
Varga
Georg
G
Higuchi
Tetsuya
T
Schwarz
Thomas
T
Sharpe
Arlene H
AH
Grabbe
Stephan
S
Bluestone
Jeffrey A
JA
Beissert
Stefan
S
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000627:therapeutic use; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D000943:Antigens, Differentiation / Q000276:immunology / Q000502:physiology*; D018122:B7-1 Antigen / Q000235:genetics / Q000502:physiology*; D051940:B7-2 Antigen; D001854:Bone Marrow Cells / Q000276:immunology; D060908:CTLA-4 Antigen; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000235:genetics; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology / Q000528:radiation effects; D014466:Ultraviolet Rays
D019138:Antibodies, Blocking; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins