The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease
Il-Kang Na, … , Nicole Beauchemin, Marcel R.M. van den Brink
Il-Kang Na, … , Nicole Beauchemin, Marcel R.M. van den Brink
Published December 1, 2009
Citation Information: J Clin Invest. 2010;120(1):343-356. https://doi.org/10.1172/JCI39395.
View: Text | PDF
Research Article

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 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.

Authors

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

×

Figure 5

tGVHD causes damage to the thymic stroma, loss of thymic epithelial cells, and cortical thinning.

Options: View larger image (or click on image) Download as PowerPoint
tGVHD causes damage to the thymic stroma, loss of thymic epithelial cell...
(A) CD45– thymic stromal cell subsets were assessed by flow cytometry in allo-BMT recipients of TCD-BM with or without WT, Trail–/–, gld, or gld/Trail–/– T cells. Absolute numbers are displayed (mean ± SEM). TCD-BM–only group, n = 9; WT T cells, n = 11; gld T cells, n = 10; Trail–/– T cells, n = 12; gld/Trail–/– T cells, n = 5. Combined data from 2 identical experiments. Endothelial cells, CD45–CD31+MHC class IIdim; fibroblasts, CD45–PDGFR1+MHC class IIneg; cTECs, CD45–CD31–MHC class IIint/hiUEA-1–; mTECs, CD45–CD31–MHC class IIint/hiUEA-1+. *P < 0.05, **P < 0.01 versus WT T cells. (B) Representative paraffin-fixed thymus sections from the groups that received TCD-BM with or without 0.25 × 106 WT, Trail–/–, gld, or gld/Trail–/– T cells were stained for K8–positive (red) cortical and K5–positive (green) medullary regions and analyzed by confocal microscopy at day 28 after transplant. Dotted lines indicate the corticomedullary junction. Solid lines indicate cortical thickness. Original magnification, ×120. Representative images are shown (n = 2–3/group). (C) Experiment was performed as in B. Three paraffin-fixed thymus sections per thymus, spaced 50 μm apart in each organ, were stained with K5 and K8 antibody and analyzed by confocal microscopy to quantitatively analyze total, medullary, and cortical areas. Averaged percent cortical area (mean ± SEM) was then determined as a fraction of total area. Symbols indicate individual animals. BM-only group, n = 5; WT and gld/Trail–/– groups; n = 8–9; combined data from 2 identical experiments. *P < 0.05 versus BM only.