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Cell Mol Life Sci. 2016 Oct;73(20):3935-47. doi: 10.1007/s00018-016-2237-7. Epub 2016 Apr 30.

Unique patterns of CD8+ T-cell-mediated organ damage in the Act-mOVA/OT-I model of acute graft-versus-host disease.

Author information

1
Hungarian Academy of Sciences-Semmelweis University, "Lendület" Experimental and Translational Immunomics Research Group, 1089, Budapest, Hungary.
2
Department of Genetics, Cell and Immunobiology, Semmelweis University, 1089, Budapest, Hungary.
3
1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085, Budapest, Hungary.
4
Csertex Research Laboratory, 1037, Budapest, Hungary.
5
"Frédéric Joliot-Curie" Institute for Radiobiology and Radiohygiene, 1221, Budapest, Hungary.
6
Hungarian Academy of Sciences-Semmelweis University, "Lendület" Experimental and Translational Immunomics Research Group, 1089, Budapest, Hungary. pos.zoltan@med.semmelweis-univ.hu.
7
Department of Genetics, Cell and Immunobiology, Semmelweis University, 1089, Budapest, Hungary. pos.zoltan@med.semmelweis-univ.hu.

Abstract

T-cell receptor (TCR)-transgenic models of acute graft-versus-host disease (aGvHD) offer a straightforward and highly controlled approach to study the mechanisms and consequences of T-cell activation following allogeneic hematopoietic stem cell transplantation (aHSCT). Here, we report that aHSCT involving OT-I mice as donors, carrying an ovalbumin-specific CD8+ TCR, and Act-mOVA mice as recipients, expressing membrane-bound ovalbumin driven by the β-actin promoter, induces lethal aGvHD in a CD8+ T-cell-dependent, highly reproducible manner, within 4-7 days. Tracking of UBC-GFP/OT-I graft CD8+ T cells disclosed heavy infiltration of the gastrointestinal tract, liver, and lungs at the onset of the disease, and histology confirmed hallmark features of gastrointestinal aGVHD, hepatic aGvHD, and aGvHD-associated lymphocytic bronchitis in infiltrated organs. However, T-cell infiltration was virtually absent in the skin, a key target organ of human aGvHD, and histology confirmed the absence of cutaneous aGVHD, as well. We show that the model allows studying CD8+ T-cell responses in situ, as selective recovery of graft CD45.1/OT-I CD8+ T cells from target organs is simple and feasible by automated tissue dissociation and subsequent cell sorting. Assessment of interferon-gamma production by flow cytometry, granzyme-B release by ELISA, TREC assay, and whole-genome gene expression profiling confirmed that isolated graft CD8+ T cells remained intact, underwent clonal expansion, and exerted effector functions in all affected tissues. Taken together, these data demonstrate that the OT-I/Act-mOVA model is suitable to study the CD8+ T-cell-mediated effector mechanisms in a disease closely resembling fatal human gastrointestinal and hepatic aGVHD that may develop after aHSCT using HLA-matched unrelated donors.

KEYWORDS:

CAG-OVA; Cytotoxic T cell; Experimental model; Homing

PMID:
27137185
DOI:
10.1007/s00018-016-2237-7
[Indexed for MEDLINE]

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