- In addition to being a carcinogen, UV is also immunosuppressive, and studies with both experimental animals and biopsy proven skin cancer patients have suggested that the immune suppression induced by UV radiation is a major risk factor for skin cancer development. Exposure of mice to subcarcinogenic doses of UV suppresses their immune response and allows for the outgrowth of UV-induced skin cancers. This immune suppression can be transferred to normal recipients by adoptive transfer of splenic CD3+, CD4+, CD8- suppressor T cells, cells that are responsible for controlling the induction of the primary tumor in the UV-irradiated host. Recent studies from this laboratory have shown that UV exposure results in the production of interleukin-10 (IL-10) by irradiated keratinocytes, which can be found in the serum of UV-irradiated mice. One consequence of increased serum IL-10 levels following UV exposure is a shift to a Th2-like immune response. This appears to result from the effect of keratinocyte-derived IL-10 on antigen presenting cell function. While spleen cells from UV-irradiated mice will not present antigen to T helper 1 (Th1) clones, the ability of these cells to present to Th2 cells is enhanced. Moreover, injecting UV-irradiated mice with antibodies to IL-10 will reverse these effects. These findings suggest that CD3+, CD4+, CD8-suppressor T eclls found in the spleens of UV-irradiated animals are Th2 cells.
The specific aims of this proposal are designed to test the hypothesis that Th2 cells are activated during UV carcinogenesis and these cells are involved in suppressing tumor immunity in the UV-irradiated mouse. The applicant proposes to determine the following: (i) Are the UV-induced T cells that prevent tumor immunity Th2 cells which mediate their suppressive effects by secreting cytokines such as IL-4 and IL-10? (ii) Can the induction of the UV-induced tumor suppressor cells be prevented by treating UV-irradiated mice with IL-12, which is known to prevent the proliferation/differentiation of Th2 cells in vivo? The long-term goal of this research is to determine how UV exposure induces systemic immune suppression and permits the outgrowth of skin cancer. Because there appears to be a link between the ability of UV exposure to induce skin cancer and interfere with immune function, it is important to study the mechanisms involved in the induction of systemic immune suppression following UV exposure to understand better one of the risk factors for skin cancer development.
