Embryonic stem cell-derived T cells induce lethal graft-versus-host disease and reject allogenic skin grafts upon thymic selection
| Autor: | Nicholas Zavazava, Ryan D. Stultz, E. M. Kim, Sabrina Bonde |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Graft Rejection
Cellular differentiation T-Lymphocytes Graft vs Host Disease Thymus Gland Biology Immunoenzyme Techniques Interleukin 21 Mice Fetus Organ Culture Techniques Cancer stem cell Immunology and Allergy Cytotoxic T cell Animals Pharmacology (medical) Receptor Notch1 Embryonic Stem Cells Interleukin 3 Homeodomain Proteins Transplantation Cell Differentiation Forkhead Transcription Factors Skin Transplantation Hematopoietic Stem Cells Endothelial stem cell embryonic structures Immunology Cancer research Interleukin 12 Stem cell Transcription Factors |
| Zdroj: | American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 12(3) |
| ISSN: | 1600-6143 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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