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

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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. and Lu, S.X. and Yim, N.L. and Goldberg, G.L. and Tsai, J. and Rao, U. and Smith, O.M. and King, C.G. and Suh, D. and Hirschhorn-Cymerman, D. and Palomba, L. and Penack, O. and Holland, A.M. and Jenq, R.R. and Ghosh, A. and Tran, H. and Merghoub, T. and Liu, C. and Sempowski, G.D. and Ventevogel, M. and 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
Publisher:American Society for Clinical Investigation
Page Range:343-356
Date:January 2010
Official Publication:https://doi.org/10.1172/JCI39395
PubMed:View item in PubMed

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