Serpin-6 expression protects embryonic stem cells from lysis by antigen-specific CTL

Area of Science:

• Immunology
• Stem Cell Biology
• Virology

Background:

• The immune response to embryonic stem (ES) cells remains incompletely understood.
• Investigating the adaptive cellular immune response to undifferentiated and differentiated ES cells infected with lymphocytic choriomeningitis virus (LCMV).

Purpose of the Study:

• To elucidate the mechanisms by which ES cells interact with the immune system, particularly cytotoxic T lymphocytes (CTLs), when infected with LCMV.

Main Methods:

• Coculturing syngeneic and allogeneic LCMV-specific CTLs with LCMV-infected undifferentiated and differentiated murine ES cells.
• Assessing IFN-gamma secretion by CTLs.
• Evaluating CTL-mediated killing of ES cells.
• Analyzing the expression of serine protease inhibitor 6 (serpin-6) in ES cells.
• Utilizing RNA interference to down-regulate serpin-6 expression.

Main Results:

• Murine ES cells, both undifferentiated and differentiated, express MHC class I molecules at low levels.
• LCMV-specific CTLs secrete IFN-gamma when cocultured with LCMV-infected ES cells, but do not efficiently kill them.
• ES cells exhibit high-level expression of serpin-6, which inhibits CTL-derived granzyme B.
• Down-regulation of serpin-6 sensitizes ES cells to CTL-induced cell death.

Conclusions:

• LCMV-infected murine ES cells present viral antigens and are recognized by LCMV-specific CTLs in an MHC class I-restricted manner.
• ES cells resist CTL-mediated lysis due to high-level expression of serpin-6.
• Serpin-6 plays a critical role in protecting ES cells from immune attack.