Spi6 in Dendritic Cell priming of CD8 T cell responses to virus

Abstract

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