Signals transmitted by binding of Fas ligand (FasL) to the Fas receptor (CD95/Apo-1) have pleiotropic effects on cellular function that present opportunities for therapeutic applications. For example, depending on the circumstances, overexpression of FasL can enhance, prevent, or reverse growth of spontaneous or transplantable tumors. Furthermore, local administration of FasL into a single paw in susceptible mice protects from or reduces the severity of collagen-induced arthritis (CIA) in all paws. Here, we define mechanisms that mediate systemic protection induced by locally delivered FasL. Protection is not solely dependent on local interactions between Fas and FasL, but rather requires induction of a paradoxical inflammatory response that not only destroys Fas-resistant tumors, but also recruits motile, activated, Fas-bearing T cells that are Fas sensitive. We demonstrate by following the antigen-specific recruitment and subsequent termination of transgenic T cells that activated T cells, including autoreactive cells responsible for CIA, are eliminated within this inflammatory environment through the overexpressed FasL. The nature of the inflammatory response, which depends on the Fas ligand being cell bound and not soluble, and the magnitude of FasL expression within the inflammatory milieu are essential for this effect, as arthritogenic inflammation alone resulting from CIA induction is insufficient to ameliorate the disease or eliminate antigen-specific T cells, even upon systemic delivery of soluble FasL. These data show that gene delivery of membrane-bound FasL can effectively recruit and eliminate autoreactive T cells.
Bibliographical noteFunding Information:
The authors wish to thank Dr. Ashley Frazer-Abel for helpful discussions. Supported by grants DK58722, JDRF 1-2001-667, the Colorado Chapter of the Arthritis Foundation, The Cancer League of Colorado, and the American Diabetes Association to DB and DK63410 to JFM. Funding also was provided to DB via SBIR grant AI47618 administered by GlobeImmune, Inc.
Copyright 2008 Elsevier B.V., All rights reserved.
- Activation-induced cell death
- Fas ligand