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

Published

Journal Article

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 alphaE and beta7, 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.

Full Text

Duke Authors

Cited Authors

  • Na, I-K; Lu, SX; Yim, NL; Goldberg, GL; Tsai, J; Rao, U; Smith, OM; King, CG; Suh, D; Hirschhorn-Cymerman, D; Palomba, L; Penack, O; Holland, AM; Jenq, RR; Ghosh, A; Tran, H; Merghoub, T; Liu, C; Sempowski, GD; Ventevogel, M; Beauchemin, N; van den Brink, MRM

Published Date

  • January 2010

Published In

Volume / Issue

  • 120 / 1

Start / End Page

  • 343 - 356

PubMed ID

  • 19955659

Pubmed Central ID

  • 19955659

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

Digital Object Identifier (DOI)

  • 10.1172/JCI39395

Language

  • eng

Conference Location

  • United States