Spi6 is a serine protease inhibitor. Its main function is inhibition of granzyme B
(GrB): it is therefore an anti-apoptotic protein in cytotoxic T cells (CTL), where
leakage of GrB from cytotoxic granules into the cytosol can trigger apoptosis. CTLs
use GrB release to kill infected cells but they can also induce apoptosis in antigenloaded
mature dendritic cells (DC) during priming. Mature DCs upregulate Spi6 and
in vitro have higher resistance to CTL-induced apoptosis compared to immature ones:
when Spi6 is absent, this resistance is lost. However, whether Spi6 protects DCs from
CTL-mediated apoptosis in vivo is still under debate. Using mice deficient in Spi6,
the project focuses on the role of Spi6 in DC survival during the priming of naïve and
memory anti-Lymphocytic Choriomeningitis virus (LCMV) CD8 T cell responses.
CD8α+ DCs are professional antigen presenting cells responsible for cross-presentation
of viral antigens in secondary lymphoid organs. Upon maturation, Spi6
is expressed by CD8α+ DC in vivo. In our model, Spi6 KO DC antigen-presentation
ability was comparable to wild-type (WT) but their survival was impaired. This
resulted in defective expansion of WT LCMV-specific CD8 T cells. A similar
requirement for Spi6 was found for DC priming of memory CD8 T cell expansion.
GrB KO CD8 T cells rescued the priming defect in Spi6 KO mice during both
primary and secondary responses, demonstrating GrB is the physiological target of
Spi6 in DCs. Thus, GrB is a major immunosuppressive agent controlling the DC
priming of anti-viral T cell mediated immunity.