TRAIL-expressing CD8+ regulatory T cells participate in the maintenance of ocular immune privilege (39.40)

Abstract

Abstract Immunological tolerance to antigens encountered in the eye, the prototypic immune privileged site, inhibits potentially damaging immune responses that would otherwise be initiated to these antigens at other anatomical locations. The induction of tolerance depends on the FasL-mediated apoptotic death of inflammatory cells that enter the eye in response to antigenic challenge. Moreover, the tolerance is not due to the failure to prime, but is mediated by the generation of CD8+ regulatory T cells (Treg) that can transfer tolerance to a naïve recipient. The present study investigated the mechanism of action of the induced CD8+ Treg. Unlike wildtype (WT) mice, TRAIL-/- or DR5-/- mice did not develop tolerance to antigen injected into the eye, even though the responding lymphocytes underwent apoptosis in the eyes of all mice. We also found that splenocytes from tolerant WT mice produced significantly less IFN, compared to TRAIL-/- mice, after restimulation. Interestingly, CD8+ T cells from TRAIL-/- mice were unable to transfer tolerance to naïve recipient WT mice, but CD8+ T cells from WT or DR5-/- mice could transfer tolerance. Subsequent investigation found that tolerant animals contained CD8+ Treg cells capable of killing antigen-pulsed splenocytes via TRAIL. Together, our data indicate that CD8+ Treg enforce tolerance in a TRAIL-dependent manner to inhibit inflammation in the eye.