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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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 1

Clinical GVHD correlates with tGVHD and thymic function of B6 → BALB/c (8.5 Gy) mice.

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Clinical GVHD correlates with tGVHD and thymic function of B6 → BALB/c (...
(A) Weight loss and (B) GVHD score. n = 6–7/group. (C) Donor BM-derived CD4+CD8+ thymocyte numbers on day 22. Dots represent groups of animals. *P < 0.05 versus TCD-BM control. n = 6–7/group. (D) Total donor splenic T cells on day 22. *P < 0.05, **P < 0.001 versus control; P values are shown for donor BM-derived T cells. n = 6–7/group. (E) Proliferation of splenic T cells after stimulation with anti-CD3 and anti-CD28 on day 22. *P < 0.05, **P < 0.001 versus control. TCD-BM only and 0.25 × 105 T cells, n = 12; 0.5 × 105 T cells, n = 6; 1 × 105 T cells, n = 3. (F) Linear regression of log-transformed thymic cellularity versus log-transformed splenic RTE numbers. Squares represent individual animals combined (n = 24) across all groups. One of two identical experiments is shown. r, regression coefficient. (G) RTEs versus the dose of donor T cells on day 42 after transplant. Dots represent individual animals. n = 4–5/group. *P < 0.05 versus recipients of TCD-BM only. (H) Histopathology (H&E) of paraffin-fixed thymus sections on day 28 (no GVHD, BM only; GVHD, BM plus 0.25 × 106 WT T cells). The dotted line indicates the corticomedullary junction. C, cortex; M, medulla. Original magnification, ×50. n = 5/group. Representative sections are shown. (I) Quantification of cortical area (% of total area) on day 28. Average of 3 sections of each organ (50 μm apart). Symbols represent individual animals. n = 4–7/group. *P = 0.01 versus recipients of TCD-BM only. All horizontal bars indicate the mean. All values are mean ± SEM.