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

Barbara Érsek, Nikolett Lupsa, Péter Pócza, Anett Tóth, Andor Horváth, Viktor Molnár, Bence Bagita, András Bencsik, H. Hegyesi, A. Matolcsy, E. Búzás, Z. Pós

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1-13
Number of pages13
JournalCellular and Molecular Life Sciences
DOIs
Publication statusAccepted/In press - Apr 30 2016

Fingerprint

Graft vs Host Disease
T-Lymphocytes
Hematopoietic Stem Cell Transplantation
Ovalbumin
T-Cell Antigen Receptor
Transplants
Liver
Histology
Granzymes
Unrelated Donors
Skin
Bronchitis
Gene Expression Profiling
Interferon-gamma
Gastrointestinal Tract
Actins
Flow Cytometry
Enzyme-Linked Immunosorbent Assay
Tissue Donors
Genome

Keywords

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

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Molecular Medicine
  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

Unique patterns of CD8+ T-cell-mediated organ damage in the Act-mOVA/OT-I model of acute graft-versus-host disease. / Érsek, Barbara; Lupsa, Nikolett; Pócza, Péter; Tóth, Anett; Horváth, Andor; Molnár, Viktor; Bagita, Bence; Bencsik, András; Hegyesi, H.; Matolcsy, A.; Búzás, E.; Pós, Z.

In: Cellular and Molecular Life Sciences, 30.04.2016, p. 1-13.

Research output: Contribution to journalArticle

Érsek, Barbara ; Lupsa, Nikolett ; Pócza, Péter ; Tóth, Anett ; Horváth, Andor ; Molnár, Viktor ; Bagita, Bence ; Bencsik, András ; Hegyesi, H. ; Matolcsy, A. ; Búzás, E. ; Pós, Z. / Unique patterns of CD8+ T-cell-mediated organ damage in the Act-mOVA/OT-I model of acute graft-versus-host disease. In: Cellular and Molecular Life Sciences. 2016 ; pp. 1-13.
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