Recent studies have shown that the expression of FasL in the eye is important to the maintenance of immune privilege. FasL induces apoptosis in Fas+ lymphoid cells that attempt to pass the blood-ocular barrier and invade the eye. FasL is clearly one of the important mediators of immune privilege that acts in concert with other factors found constitutively in the eye to preserve vision. Although a number of studies have examined the expression of FasL in immune privileged sites, insight into how expression is regulated has been lacking. This has hampered elucidation of important mechanisms much beyond the phenomenological stage, as function is often inferred from RT-PCR data, in vitro cell lines, or unreliable antibodies. In this application, we will continue to explore the regulation of FasL expression using novel mouse strains that will give us a unique look at FasL and the eye.
In specific aim 1, we will use recently developed mouse strains to explore FasL expression in the eye. These strains include a FasL promoter-luciferase reporter strain, a FasL-eYFP """"""""knock-in"""""""" strain, and a FasL-flox strain.
In aim 2, we will explore the apparent resistance of activated T-cells to killing by ocular FasL. These studies will examine T cells obtained from TCR -transgenic mice, as well as those activated to an ocular autoantigen.
Aim 3 will further define the role of TRAIL (for TNF-related apoptosis inducing ligand) in the eye. Preliminary studies suggest that it may protect the eye from invasion by tumor cells.
In aim 4, we will continue to explore the role of apoptosis and apoptotic cells in regulation of the immune response. Here, we will use a unique approach to define regulatory T cells and identify antigen-presenting cells involved in peripheral tolerance. We believe that the completion of these aims in this application will permit us to better understand important mechanisms that protect the eye and maintain the visual axis.
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