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

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Figure 4

Soluble DR5 agonists are sufficient to damage the thymus after allo-BMT in 5×106 B6 CD45.1 + TCD-BM only → BALB/c (8.5 Gy) mice.

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Soluble DR5 agonists are sufficient to damage the thymus after allo-BMT ...
Recipients were treated with 200 μg hamster IgG control antibody or DR5-1 agonistic antibody i.p. on days –1, 1, 3, and 5 peritransplant (A–E) or on days 10, 12, 14, and 16 after transplant (F–J). Recipients were analyzed at day 28 after transplant. Symbols represent individual animals (mean ± SEM). *P < 0.05, **P < 0.01 versus hamster IgG; combined data from 2 independent experiments. (A) Total thymocytes and (B) donor BM-derived CD45.1+CD4+CD8+ (DP) thymocytes. DR5-1, n = 11; hamster IgG, n = 15. (C) Total BM cells. n = 4–5/group. (D) Donor LSK cells from the BM. n = 4–5/group. (E) Donor splenic CD45.1+CD3ε+ T cells. DR5-1, n = 11; hamster IgG, n = 15. (F) Total thymocytes and (G) donor BM-derived CD45.1+CD4+CD8+ (DP) thymocytes. DR5-1, n = 5/group. (H) Total BM cells. n = 5/group. (I) Donor LSK cells from the BM. n = 5/group. (J) Donor splenic CD45.1+CD3ε+ T cells. n = 5/group. (K) Mice were transplanted as above. Thymi from recipients of hamster IgG control antibody only were harvested at day 28, stained with anti-DR5 antibody, and gated for donor CD45.1+ thymocytes subsets (CD4–CD8–, CD4+CD8+, CD4+CD8–, and CD4–CD8+) as shown. The percentage of cells that are DR5 positive was determined based on an isotype control gate set at less than 0.25% positive. n = 5/group. Horizontal bars indicates the mean. DN, CD4+CD8+ double negative.