The T Cell Cytolytic Molecules FasL and TRAIL are Required for Thymic GVHD (141.14)

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Abstract Thymic graft-versus-host-disease (tGVHD) is an important contributor to impaired T cell reconstitution in patients with GVHD. We analyzed molecules relevant for T cell trafficking and cytolytic function in tGVHD. Thymic output and cellularity were inversely proportional to numbers of mature donor T cells in the allograft, suggesting that tGVHD severity was inversely associated with thymic function. Upon adoptive transfer of CFSE-labeled donor T cells, we noted that thymus-infiltrating alloreactive donor T cells were largely fast-proliferating and highly activated. These T cells infiltrated the thymus within one week after allogeneic bone marrow transplantation. We analyzed T cells in tGVHD with mice deficient for certain molecules, and found that the trafficking molecules CCR9, β7 integrin, and PSGL-1 were all partially required for tGVHD, while L-selectin and αE integrin subunit may be dispensable. Similarly, we examined the role of T cell cytolytic pathways for tGVHD, and found that FasL and tumor necrosis factor associated apoptosis inducing ligand (TRAIL) were required for tGVHD, but that perforin and TNF were dispensable. As host thymic stroma may be an important target for donor alloreactive T cells, we assessed the expression of the death receptors Fas and DR5 in thymic stroma from normal and irradiated mice, and found that endothelium and fibroblasts, as well as epithelial cells upregulated the expression of both Fas and DR5 after irradiation. FLIP, which is a negative regulator of Fas ligand and TRAIL mediated apoptosis, was also downregulated after irradiation. Our study suggests that TRAIL, which has previously been shown to be important in graft-versus-tumor activity, may also be important for mediating GVHD.