The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease.

Na, Il-Kang; Lu, Sydney X; Yim, Nury L; Goldberg, Gabrielle L; Tsai, Jennifer; Rao, Uttam; Smith, Odette M; King, Christopher G; Suh, David; Hirschhorn-Cymerman, Daniel; Palomba, Lia; Penack, Olaf; Holland, Amanda M; Jenq, Robert R; Ghosh, Arnab; Tran, Hien; Merghoub, Taha; Liu, Chen; Sempowski, Gregory D; Ventevogel, Melissa; Beauchemin, Nicole; van den Brink, Marcel R M

Thymic graft-versus-host disease (tGVHD) can contribute to profound T cell deficiency and repertoire restriction after allogeneic BM transplantation (allo-BMT). However, the cellular mechanisms of tGVHD and interactions between donor alloreactive T cells and thymic tissues remain poorly defined. Using clinically relevant murine allo-BMT models, we show here that even minimal numbers of donor alloreactive T cells, which caused mild nonlethal systemic graft-versus-host disease, were sufficient to damage the thymus, delay T lineage reconstitution, and compromise donor peripheral T cell function. Furthermore, to mediate tGVHD, donor alloreactive T cells required trafficking molecules, including CCR9, L selectin, P selectin glycoprotein ligand-1, the integrin subunits alphaE and beta7, CCR2, and CXCR3, and costimulatory/inhibitory molecules, including Ox40 and carcinoembryonic antigen-associated cell adhesion molecule 1. We found that radiation in BMT conditioning regimens upregulated expression of the death receptors Fas and death receptor 5 (DR5) on thymic stromal cells (especially epithelium), while decreasing expression of the antiapoptotic regulator cellular caspase-8-like inhibitory protein. Donor alloreactive T cells used the cognate proteins FasL and TNF-related apoptosis-inducing ligand (TRAIL) (but not TNF or perforin) to mediate tGVHD, thereby damaging thymic stromal cells, cytoarchitecture, and function. Strategies that interfere with Fas/FasL and TRAIL/DR5 interactions may therefore represent a means to attenuate tGVHD and improve T cell reconstitution in allo-BMT recipients.