Embryonic Stem Cell-Derived T Cells Induce Lethal Graft-Versus-Host Disease and Reject Allogenic Skin Grafts upon Thymic Selection

作者：Kim E M; Stultz R; Bonde S; Zavazava N^*

来源：American Journal of Transplantation, 2012, 12(3): 600-609.

DOI：10.1111/j.1600-6143.2011.03845.x

• Acute graft-versus-host disease
• HoxB4
• stem cells
• skin allograft
• T cells

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 V beta 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.

• 出版日期2012-3