Induction of Stable Mixed Chimerism by Embryonic Stem Cells Requires Functional Fas/FasL Engagement

Abstract

These data suggest a critical role for Fas-FasL engagement in ESC engraftment. We conclude that ESC may induce clonal deletion of alloreactive T cells by Fas-induced apoptosis in recipient T cells, protecting them from rejection. The data provide a rationale for improved protocols for the achievement of robust ESC-induced mixed chimerism.

Immunological Barriers to Embryonic Stem Cell-Derived Therapies

“…However, Koch et al [2007] demonstrated that ES cells suppress T cell proliferation in a contact-independent manner by secreting TGF-␤ . The mechanism proposed to mediate contact-dependent suppression of T cells is the induction of clonal deletion of alloreactive T cells by Fas-mediated apoptosis triggered by FasL expressed on ES cells [Fabricius et al, 2005]. However, 2 other reports provide evidence against this mechanism in murine ES cells [Brunlid et al, 2007;Koch et al, 2007].…”

“…Lysis of murine ES cells was mediated in this case most likely by the combination of 2 factors: very low expression on ES cells of NK cell inhibitory MHC class I molecules and high expression of retinoic acid early inducible-1 (Rae-1) family of proteins, which serve as high-affinity ligands for the NK cell-activating receptor NKG2D [Bonde and Zavazava, 2006]. Similarly, in vitro generated alloreactive CTLs were not cytolytic against unstimulated murine ES cells, but were able to slightly lyse only the IFN-␥ -treated ES cells [Fabricius et al, 2005;Bonde and Zavazava, 2006]. In our hands, LCM virus-infected or peptide-loaded murine ES cells and their early differentiated progeny (embryoid body-derived cells on days 5 and 8 of differentiation) were also resistant to killing by activated LCM virusspecific syngeneic CTLs [Abdullah et al, 2007].…”

“…Low-level expression of MHC class I molecules on murine and human ES cells and their progeny prompted some investigators to predict that this may not be sufficient for effective recognition and killing of ES cells by CD8+ lymphocytes [Magliocca et al, 2006] or for rejection of ES cells by allogeneic recipients [Fabricius et al, 2005;Bonde and Zavazava, 2006]. However, it is very well established by several elegant studies that the number of ligands on APCs and target cells required for T cell recognition, activation and killing is extremely low.…”

“…In addition, human and murine ES cells are capable of actively modulating immune reactions as demonstrated by their ability to inhibit third-party allogeneic dendritic cell-mediated T cell proliferation [Li et al, 2004], to abrogate ongoing alloresponses in mixed lymphocyte reactions [Bonde and Zavazava, 2006;Koch et al, 2007] and to completely prevent T cell cytotoxicity against allogeneic ConA blasts in vitro [Fabricius et al, 2005]. In 2 studies, these phenomena were not mediated by soluble factors but rather by a process that requires direct cell-to-cell contact [Li et al, 2004;Fabricius et al, 2005]. However, Koch et al [2007] demonstrated that ES cells suppress T cell proliferation in a contact-independent manner by secreting TGF-␤ .…”

Progress and prospects: gene transfer into embryonic stem cells

“…For example, rat or mouse ES-derived hematopoietic cells can survive engraftment in a xenogenic or fully mismatched environment without immunosuppression. 55,66,67 This property may be due to the embryonic nature of ESCs, and seems to be conserved in hESCs. Li et al 68 have shown that hESCs and their derivatives can evade both in vivo xenogenic and in vitro allogeneic immune responses despite normal levels of MHCI.…”