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 January 4, 2010; First published December 1, 2009
Citation Information: J Clin Invest. 2010;120(1):343-356. https://doi.org/10.1172/JCI39395.
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Categories: Research Article Transplantation

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

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Figure 3

Alloreactive T cells require FasL and TRAIL to mediate tGVHD.

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Alloreactive T cells require FasL and TRAIL to mediate tGVHD. (A) BM-der...
(A) BM-derived CD4+CD8+ (DP) thymocytes in recipients of B6 CD45.1 TCD-BM with or without 0.25 × 106 B6 versus B6.KO (deficient for cytolytic molecules) donor T cells on day 28. BM only, n = 18; WT T cells, n = 21; gld (FasL deficient), n = 8; Trail–/–, n = 8; gld/Trail–/–, n = 7; gld/Trail–/–Tnf–/–, n = 6; Pfp–/–, n = 12; Tnf–/–, n = 12; Ifng–/–, n = 16; combined data from 2 independent experiments. (B) Experiment as in A with 0.5 × 106 donor T cells. BM only, n = 22; WT T cells, n = 20; gld, n = 13; Trail–/–, n = 13; gld/Trail–/–Tnf–/–, n = 13; Pfp–/–, n = 12; Ifng–/–, n = 9; combined data from 2 to 3 independent experiments. (A and B) *P < 0.05, **P < 0.01 versus WT. (C) Thymic architecture of thymus sections from A were analyzed (H&E, day 28). Representative sections are shown. Original magnification, ×50. n = 5/group. (D) Total thymocyte counts in mice that received B6 BM with or without 0.25 × 106 CD5+ B6 WT CD4, WT CD8, Trail–/– CD4, Trail–/– CD8, gld CD4, or gld CD8 T cells. Symbols represent individual animals (mean ± SEM). *P < 0.05. n = 6–7/group. (E) Absolute numbers of BM-derived CD45.1+CD4+CD8+ thymocytes in lpr (Fas receptor deficient) and WT B6 recipients on day 28. Symbols represent individual animals (mean ± SEM). n = 8/group. **P < 0.01 versus corresponding WT controls. (F) Total thymocytes in recipients of lpr or WT B6 TCD-BM and T cells on day 28. Dots represent individual animals. Horizontal bars indicate the mean (A, B, and F). n = 8–10/group.