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An Important Role of CD80/CD86-CTLA-4 Signaling during Photocarcinogenesis in Mice¹

Karin Loser^*, Andrea Scherer^*, Mathias B. W. Krummen^*, Georg Varga^*, Tetsuya Higuchi^*, Thomas Schwarz^*,¶, Arlene H. Sharpe, Stephan Grabbe, Jeffrey A. Bluestone and Stefan Beissert^1,2,*,

^* Department of Dermatology, University of Munster, Munster Germany; Department of Pathology, Harvard University, Boston, MA 02116; Diabetes Research Center, University of California, San Francisco, CA 94143; Department of Experimental Immunology, German Research Center for Biotechnology, Braunschweig, Germany; and ^¶ Department of Dermatology, University of Kiel, Kiel, Germany

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.

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				K. Loser, J. Apelt, M. Voskort, M. Mohaupt, S. Balkow, T. Schwarz, S. Grabbe, and S. Beissert IL-10 Controls Ultraviolet-Induced Carcinogenesis in Mice J. Immunol., July 1, 2007; 179(1): 365 - 371. [Abstract] [Full Text] [PDF]