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| Item Type: | Article |
|---|---|
| Title: | The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease |
| Creators Name: | Na, I.K., Lu, S.X., Yim, N.L., Goldberg, G.L., Tsai, J., Rao, U., Smith, O.M., King, C.G., Suh, D., Hirschhorn-Cymerman, D., Palomba, L., Penack, O., Holland, A.M., Jenq, R.R., Ghosh, A., Tran, H., Merghoub, T., Liu, C., Sempowski, G.D., Ventevogel, M., Beauchemin, N. and van den Brink, M.R.M. |
| Abstract: | 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. |
| Keywords: | Bone Marrow Transplantation, CASP8 and FADD-Like Apoptosis Regulating Protein, Cell Movement, Fas Ligand Protein, Graft vs Host Disease, Homologous Transplantation, Lymphocyte Activation, OX40Receptors, Stromal Cells, Thymus Gland, T-Lymphocytes, TNF-Related Apoptosis-Inducing Ligand Receptors, Animals, Mice |
| Source: | Journal of Clinical Investigation |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Volume: | 120 |
| Number: | 1 |
| Page Range: | 343-356 |
| Date: | January 2010 |
| Official Publication: | https://doi.org/10.1172/JCI39395 |
| PubMed: | View item in PubMed |
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