title: IL-17-dependent, IFN-gamma-independent tumor rejection is mediated by cytotoxic T lymphocytes and occurs at extraocular sites, but is excluded from the eye.
abstract: Although intraocular tumors reside in an immune-privileged site where immune responses are suppressed, some tumors are rejected. An example of this is the rejection of intraocular adenovirus-induced (adenovirus type 5 early region 1 [Ad5E1]) tumors in C57BL/6 mice. We previously identified an Ad5E1 tumor clone in which the rejection is IFN-γ dependent and culminates in the destruction of both the tumor and the eye. Although Ad5E1 tumors are not rejected when transplanted into the eyes of IFN-γ KO mice, they are rejected after s.c. transplantation. Thus, outside of the eye Ad5E1 tumors elicit a form of tumor immunity that is IFN-γ independent. In this article, we demonstrate that IFN-γ-independent s.c. rejection requires both CD4(+) and CD8(+) T cells. Furthermore, s.c. tumor rejection requires IL-17, which is produced by IFN-γ-deficient CD4(+) T cells in response to tumor Ags (TAs). Splenocytes from CD4-depleted IFN-γ KO mice produce significantly less IL-17 compared with splenocytes from isotype-treated IFN-γ KO animals in response to TAs. Furthermore, depletion of IL-17 decreases CTL activity against Ad5E1 tumor cells. In this model we propose that, in the absence of IFN-γ, CD4(+) T cells produce IL-17 in response to TAs, which increases CTL activity that mediates tumor rejection; however, this does not occur in the eye. IL-6 production within the eye is severely reduced, which is consistent with the failure to induce Th17 cells within the intraocular tumors. In contrast, the s.c. environment is replete with IL-6 and supports the induction of Th17 cells. Therefore, IFN-γ-independent tumor rejection is excluded from the eye and may represent a newly recognized form of ocular immune privilege.
authors.affiliation: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Terry G
authors.initials: TG
authors.lastname: Coursey
authors.forename: Peter W
authors.initials: PW
authors.lastname: Chen
authors.forename: Jerry Y
authors.initials: JY
authors.lastname: Niederkorn
mesh_terms: D000818:Animals; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005123:Eye / Q000276:immunology*; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D020381:Interleukin-17; D007371:Interferon-gamma