Rejection of Intraocular Tumors by CD4+ T Cells Without Induction of Phthisis

Abstract

Immune privilege of the eye protects against sight-threatening inflammatory events, but can also permit outgrowth of otherwise nonlethal immunogenic tumors. Nonetheless, ocular tumor growth can be controlled by cellular immune responses. However, this will normally result in phthisis of the eye, in case tumor rejection is mediated by a delayed-type hypersensitivity response orchestrated by CD4+ T cells. We now show that intraocular tumors can be eradicated by CD4+ Th cells without inducing collateral damage of neighboring ocular tissue. Injection of tumor cells transformed by the early region 1 of human adenovirus type 5 in the anterior chamber of the eye leads to intraocular tumor formation. Tumor growth is transient in immunocompetent mice, but lethal in immunodeficient nude mice, indicating that T cell-dependent immunity is responsible for tumor clearance. Tumor rejection has all the characteristics of a CD8+ T cell-mediated immune response, as the tumor did not express MHC class II and only tumor tissue was the subject of destruction. However, analysis of the molecular and cellular mechanisms involved in tumor clearance revealed that perforin, TNF-α, Fas ligand, MHC class I, and CD8+ T cells did not play a crucial role in tumor eradication. Instead, effective tumor rejection was entirely dependent on CD4+ Th cells, as CD4-depleted as well as MHC class II-deficient mice were unable to reject their intraocular tumor. Taken together, these observations demonstrate that CD4+ T cells are able to eradicate MHC class II-negative tumors in an immune-privileged site without affecting surrounding tissues or the induction of phthisis.

CD8+ T Cells Circumvent Immune Privilege in the Eye and Mediate Intraocular Tumor Rejection by a TNF-α-Dependent Mechanism

“…The rejection of intraocular Ad5E1 tumors is unique, as it appears to be primarily mediated by CD4 ϩ T cells and not CD8 ϩ T cells (9). Although intraocular Ad5E1 tumors undergo rejection in mice depleted of CD8 ϩ T cells (9), there is evidence that CD8 ϩ T cells might play an ancillary role in Ad5E1 tumor rejection. Schurmans et al indicated that CD8 ϩ T cells were present in intraocular Ad5E1 tumors (9).…”

“…Once CD8 ϩ T cells are primed, the depletion of CD4 ϩ T cells does not affect the effector function of CD8 ϩ T cells (26). The rejection of intraocular Ad5E1 tumors is unique, as it appears to be primarily mediated by CD4 ϩ T cells and not CD8 ϩ T cells (9). Although intraocular Ad5E1 tumors undergo rejection in mice depleted of CD8 ϩ T cells (9), there is evidence that CD8 ϩ T cells might play an ancillary role in Ad5E1 tumor rejection.…”

“…Although intraocular Ad5E1 tumors undergo rejection in mice depleted of CD8 ϩ T cells (9), there is evidence that CD8 ϩ T cells might play an ancillary role in Ad5E1 tumor rejection. Schurmans et al indicated that CD8 ϩ T cells were present in intraocular Ad5E1 tumors (9). Moreover, they demonstrated that a CD8 ϩ CTL clone generated by s.c. immunization with adenovirus ϩ Ras-transformed Ad5E1 tumor cells was capable of mediating the rejection of established intraocular Ad5E1 tumors when adoptively transferred into syngeneic C57BL/6 mice (8).…”

“…Tumor rejection requires CD4 ϩ T cells, IFN-␥, and macrophages, but does not require TNF-␣, FasL, TRAIL, perforin, B cells, NK cells, or CD8 ϩ T cells (9 -11, 18). Importantly, tumor rejection does not culminate in phthisis and instead the anatomical integrity of the eye is left intact (9).…”

“…However, ocular immune privilege can be circumvented. Ocular tumors can induce a robust systemic immune response that culminates in tumor rejection (7)(8)(9)(10)(11). Immune rejection of intraocular tumors follows two mutually divergent patterns.…”