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Ludwig-Boltzmann Institute for Cell Biology and Immunobiology of the Skin, Department of Dermatology, University of Münster, Münster, Germany; and
Ben May Institute for Cancer Research, University of Chicago, Chicago, IL 60637
Immunosuppression by UV light contributes significantly to the
induction of skin cancer by suppressing the cell-mediated immune
responses which control the development of carcinogenesis. The
B7/CD28-CTLA-4 signaling pathway provides costimulatory signals
essential for Ag-specific T cell activation. To investigate the role of
this pathway in photocarcinogenesis, we utilized transgenic (Tg) mice
which constitutively express CTLA-4Ig, a high-affinity CD28/CTLA-4
antagonist that binds to both B7-1 and B7-2. The transgene is driven by
a skin-specific promoter yielding high levels of CTLA-4Ig in the skin
and serum. Chronic UV exposure of CTLA-4Ig Tg mice resulted in
significantly reduced numbers of skin tumors, when compared to control
mice. In addition, Tg mice were resistant to UV-induced suppression of
delayed-type hypersensitivity responses to alloantigens. Most
importantly, upon stimulation with mitogens and alloantigens, T cells
isolated from CTLA-4Ig Tg mice produced significantly less IL-4 but
more IFN-
compared to control T cells, suggesting an impaired Th2
response and a relative increase of Th1-type immunity. Together, these
data show that overall B7 engagement directs immune responses toward
the Th2 pathway. Moreover, they point out the crucial role of Th1
immune reactions in the protection against
photocarcinogenesis.
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