CD4+ T-Cell–Mediated Mechanisms of Corneal Allograft Rejection: Role of Fas-Induced Apoptosis

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Abstract

Background.

The role of CD4+ T cells as effector cells in corneal allograft rejection is poorly understood. We investigated the role of CD4+ T cells as helper cells in the generation of allospecific effector macrophages in corneal graft rejection and the role of CD4+ T cells as apoptosis-inducing effector cells.

Methods.

Corneal allografts were transplanted to CD4 knockout, FasL-deficient, and macrophage-depleted hosts. An Annexin-V binding assay was used to evaluate the susceptibility of corneal cells to both Fas-dependent and CD4+ T-cell–mediated apoptosis in vitro.

Results.

Macrophages were essential for graft rejection, but not as effector cells. Anti-BALB/c CD4+ T cells from immunized C57BL/6 mice induced apoptosis of BALB/c corneal epithelial and endothelial cells. However, anti-BALB/c CD4+ T cells from FasL-deficient gld/gld mice did not induce apoptosis of BALB/c corneal endothelial cells. Moreover, gld/gld mice had a reduced capacity to reject BALB/c corneal allografts. Although the initial results suggested a role for Fas-induced apoptosis in corneal graft rejection, additional experiments indicated otherwise. The incidence and tempo of immune rejection of Fas-deficient lpr/lpr corneal allografts were no different than those for corneal grafts from Fas-bearing C57BL/6 donors. Moreover, CD4+ T-cell–mediated apoptosis of corneal cells could not be blocked with either Fas-Fc fusion protein or anti-FasL blocking antibody.

Conclusions.

The results suggest that CD4+ T cells function directly as effector cells and not as helper cells in the rejection of corneal allografts. Although the corneal endothelium is highly susceptible to Fas-induced apoptosis, this is apparently not the primary mechanism of CD4+ T-cell–dependent rejection.

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