The Role of Interferon-Gamma, Cd4-Positive T Cells, and Cd8-Positive T Cells in the Immune Rejection of Intraocular Tumors
Dace, Dru Samuel
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Although the eye is an immune privileged site, intraocular tumors can sometimes be rejected by the immune system. Ad5E1 is an adenoviral gene-transformed tumor cell line that is rejected by the immune system when transplanted into the anterior chamber of the eye in syngeneic C57BL/6 mice. Two components of the immune system have been shown to be absolutely necessary for intraocular tumor rejection: CD4+ T cells and IFN-gamma , as mice deficient in these components cannot reject the tumor. This study further examined the role of IFN-gamma and CD4+ T cells in mediating rejection of intraocular Ad5E1 tumors, and examined the ancillary role of CD8+ T cells. IFN-gamma acted directly on Ad5E1 tumor cells and not host cells. The anti-tumor effects of IFN-gamma were multiple, as IFN-gamma induced tumor cell apoptosis and inhibited tumor cell proliferation. Also, IFN-gamma promoted tumor rejection by inhibiting angiogenesis, since IFN-gamma KO mice demonstrated increased tumor blood vessel density and IFN-gamma induced the up-regulation of 5 anti-angiogenic genes and the down-regulation of 4 pro-angiogenic genes in Ad5E1 tumor cells. CD4+ T cells infiltrated intraocular Ad5E1 tumors. Following rejection of Ad5E1 tumors in C57BL/6 mice, CD4+ T cells could be adoptively transferred to SCID mice and induce Ad5E1 tumor rejection. CD4+ T cell derived IFN-gamma might mediate tumor rejection, as these cells produce significant levels of IFN-gamma in response to Ad5E1 tumor antigens. Macrophages were necessary for CD4+ T cells to mediate rejection, as mice depleted of ocular macrophages developed progressively growing intraocular Ad5E1 tumors. CD8+ T cells were not required for rejection, as CD8+ T cell-depleted and CD8+ T cell KO mice rejected Ad5E1 tumors. However, CD8+ T cells infiltrated intraocular Ad5E1 tumors. Following rejection in C57BL/6 mice, CD8+ T cells could be adoptively transferred to SCID mice and protected them from Ad5E1 tumor growth, similar to the effect produced by adoptively transferred CD4+ T cells. In attempting to ascertain what CD8+ T cells utilize to mediate Ad5E1 tumor rejection, I determined that TNF-alpha was required for tumor rejection, but IFN-gamma , FasL, perforin, TRAIL and CTL activity were not necessary for CD8+ T cell-mediated tumor rejection.