title: Embryonic stem cell-derived T cells induce lethal graft-versus-host disease and reject allogenic skin grafts upon thymic selection.
abstract: Efficient differentiation of embryonic stem cells (ESC) into hematopoietic progenitor cells (HPCs) is crucial for the establishment of stem cell-based therapies targeting the treatment of immunological and hematological disorders. However, so far, it has not been possible to induce long-term survival of murine ESC-derived HPCs without the overexpression of HoxB4, a homeobox transcription factor that confers self-renewal properties to hematopoietic cells. Yet it has not been feasible to generate T cells from HoxB4-expressing HPCs, a problem that has been attributed to HoxB4. Here, we show that Notch1 signaling in HoxB4-transduced ESCs leads to efficient derivation of T cells that survive long term. These T cells display a normal T-cell Vβ repertoire, respond to mitogen stimulation and induce lethal graft-versus-host disease. Thymic selection in fetal thymic organ cultures (FTOCs) allowed negative selection and generation of T cells tolerant to 'self' and capable of rejecting MHC-mismatched skin allografts. Our data show that ESC-derived T cells, despite high expression of HoxB4, are fully immunocompetent.
authors: Department of Internal Medicine, University of Iowa and Veterans Affairs Medical Center, Iowa City, IA, USA.
authors: E M
authors: EM
authors: Kim
authors: R
authors: R
authors: Stultz
authors: S
authors: S
authors: Bonde
authors: N
authors: N
authors: Zavazava
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000276:immunology*; D005333:Fetus / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006084:Graft Rejection / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006086:Graft vs Host Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology*; D018398:Homeodomain Proteins / Q000378:metabolism; D007124:Immunoenzyme Techniques; D051379:Mice; D009924:Organ Culture Techniques; D051881:Receptor, Notch1 / Q000378:metabolism; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018398:Homeodomain Proteins; C513262:Hoxb4 protein, mouse; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D014157:Transcription Factors