Membrane Fas ligand activates innate immunity and terminates ocular immune privilege.
It has been proposed that the constitutive expression of Fas ligand (FasL) in the eye maintains immune privilege, in part through inducing apoptosis of infiltrating Fas(+) T cells. However, the role of FasL in immune privilege remains controversial due to studies that indicate FasL is both pro- and anti-inflammatory. To elucidate the mechanism(s) by which FasL regulates immune privilege, we used an ocular tumor model and examined the individual roles of the membrane-bound and soluble form of FasL in regulating ocular inflammation. Following injection into the privileged eye, tumors expressing only soluble FasL failed to trigger inflammation and grew progressively. By contrast, tumors expressing only membrane FasL 1) initiated vigorous neutrophil-mediated inflammation, 2) terminated immune privilege, and 3) were completely rejected. Moreover, the rejection coincided with activation of both innate and adaptive immunity. Interestingly, a higher threshold level of membrane FasL on tumors is required to initiate inflammation within the immune privileged eye, as compared with nonprivileged sites. The higher threshold is due to the suppressive microenvironment found within aqueous humor that blocks membrane FasL activation of neutrophils. However, aqueous humor is unable to completely block the proinflammatory effects of tumor cells that express high levels of membrane FasL. In conclusion, our data indicate that the function of FasL on intraocular tumors is determined by the microenvironment in conjunction with the form and level of FasL expressed.
Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
Meredith S
MS
Gregory
Amanda C
AC
Repp
Andreas M
AM
Holhbaum
Rebecca R
RR
Saff
Ann
A
Marshak-Rothstein
Bruce R
BR
Ksander
D000818:Animals; D000867:Anterior Chamber / Q000276:immunology / Q000473:pathology; D001082:Aqueous Humor / Q000276:immunology; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis; D004306:Dose-Response Relationship, Immunologic; D005123:Eye / Q000276:immunology* / Q000473:pathology; D005134:Eye Neoplasms / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D053222:Fas Ligand Protein; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology; D007113:Immunity, Innate / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007940:Leukemia L5178 / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D019463:Mice, Inbred MRL lpr; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D011817:Rabbits; D013045:Species Specificity; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D019014:fas Receptor / Q000378:metabolism*
D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007375:Interleukin-1; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor