Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 120, Issue 1, Pages 343-356Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI39395
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Funding
- NIH [R01-HL069929, R01-CA107096, R01-AI080455, P01-CA33049, T32 AI07621]
- Ryan Gibson Foundation (Dallas, Texas, USA)
- Elsa U. Pardee Foundation (Midland, Michigan, USA)
- Byrne Foundation (Etna, New Hampshire, USA)
- Emerald Foundation (New York, New York, USA)
- Commonwealth Foundation for Cancer Research (Richmond, Virginia, USA)
- Bobby Zucker Memorial Fund (Phoenixville, Pennsylvania, USA)
- Lymphoma Foundation (New York, New York, USA)
- Canadian Institutes of Health Research
- Deutsche Krebshilfe
- Mildred-Scheel-Stiftung
- Deutsche Forschungsgemeinschaft
- Starr Stem Cell Scholar Fellowship Awardee
- American Association for Cancer Research MedImmune Fellowship for Research on Biologics-Based Therapies for Cancer (Philadelphia, Pennsylvania, USA)
- Leukemia & Lymphoma Society Special Fellowship in Clinical Research (White Plains, New York, USA)
- NATIONAL CANCER INSTITUTE [P30CA008748, R01CA107096, P01CA033049] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL069929] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [UC6AI058607, T32AI007621, R01AI080455] Funding Source: NIH RePORTER
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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 alpha(E) and beta(7), 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.
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