The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease Journal Article
| Authors: | 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.; van den Brink, M. R. M. |
| Article Title: | The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease |
| 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 αE and β7, 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 apoptosisinducing 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: | controlled study; transplantation, homologous; drug potentiation; nonhuman; t lymphocyte; t-lymphocytes; animal cell; mouse; animal; cytology; animals; mice; cell function; carcinoembryonic antigen related cell adhesion molecule 1; radiation; fas ligand; animal experiment; animal model; cell motion; protein interaction; mice, inbred balb c; mice, inbred c57bl; physiology; c57bl mouse; immunology; lymphocyte activation; donor; bagg albino mouse; pre t lymphocyte; thymus; thymus gland; death receptor 5; tumor necrosis factor related apoptosis inducing ligand; graft versus host reaction; cell movement; cytolysis; caspase 8; fas ligand protein; upregulation; bone marrow transplantation; graft vs host disease; stroma cell; stromal cells; cd134 antigen; receptors, ox40; chemokine receptor ccr2; graft recipient; allotransplantation; lymphocyte function; alloimmunity; tnf-related apoptosis-inducing ligand; p selectin glycoprotein ligand 1; alpha integrin; beta7 integrin; chemokine receptor ccr9; chemokine receptor cxcr3; inhibitor protein; l selectin; flice inhibitory protein; tnfrsf4 protein, mouse; tnfsf10 protein, mouse; tumor necrosis factor related apoptosis inducing ligand receptor; conditioning; cytoarchitecture; thymus graft; casp8 and fadd-like apoptosis regulating protein; receptors, tnf-related apoptosis-inducing ligand |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 120 |
| Issue: | 1 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2010-01-04 |
| Start Page: | 343 |
| End Page: | 356 |
| Language: | English |
| DOI: | 10.1172/jci39395 |
| PUBMED: | 19955659 |
| PROVIDER: | scopus |
| PMCID: | PMC2798682 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 20 April 2011" - "CODEN: JCINA" - "Source: Scopus" |
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