Serine proteases are important components of the immune system, playing a role in many processes including migration, phagocytosis and elimination of virally infected and cancerous cells. Members of the serpin superfamily regulate the activity of these proteases to limit tissue damage and unwarranted cell death. This review focuses on the role of intracellular (clade B) serpins in maintaining viability of both innate and adaptive immune cells.

Serpinb9 (Sb9, also called Spi6) is an intracellular inhibitor of granzyme B (GrB) that protects activated cytotoxic lymphocytes from apoptosis. We show here that the CD8 þ subset of splenic dendritic cells (DC), specialized in major histocompatibility complex class I (MHC I) presentation of exogenous antigens (cross-presentation), produce high levels of Sb9. Mice deficient in Sb9 are unable to generate a cytotoxic T-cell response against cell-associated antigen by cross-presentation, but maintain normal MHC-II presentation to helper T cells. This impaired cross-priming ability is autonomous to DC and is evident in animals deficient in both Sb9 and GrB, indicating that this role of Sb9 in DC is GrB-independent. In Sb9-deficient mice, CD8 þ DC develop normally, survive as well as wild-type DC after antigenic challenge, and exhibit unimpaired capacity to take up antigen. Although the core processing machinery is unaffected, Sb9-deficient DC appear to process antigen faster. Our results point to a novel, GrB-independent role for Sb9 in DC cross-priming. Keywords: cross-presentation; dendritic cells; serpinb9Dendritic cells (DC) are professional antigen-presenting cells with a crucial role in induction of immunity and tolerance. DC can be split into two major functional subsets: CD8 þ DC, which cross-present extracellular antigen on major histocompatibility complex class I (MHC I) molecules to activate cytotoxic T cells (CTL), 1,2 and CD8 À DC, which capture and present extracellular antigen only in the context of MHC-II. 3 Underpinning this functional dichotomy are differences in the way these two DC subsets handle endocytosed antigen.As in other antigen-presenting cells, antigens internalised by both CD8 þ and CD8 À DC are degraded by endolysosomal proteases, 4 generating antigenic peptides that are bound by MHC-II molecules and then exposed on the DC surface as MHC-II-peptide complexes for CD4 T-cell recognition. The CD8 þ DC differ from the CD8 À DC in that they also deliver endocytosed antigens to the cytosol for degradation by the proteasome. The resulting peptides enter the endoplasmic reticulum through the transporter associated with antigen processing, 5 and bind MHC I molecules, which then move to the cell surface via the conventional secretory pathway. Once at the surface, MHC I-peptide complexes are recognised by CD8 þ CTL. The special ability of CD8 þ DC to present exogenous antigens via MHC I molecules is called cross-presentation, and it has a crucial role in induction of CTL responses against viruses, other pathogens and autoantigens. 6 Why CD8 þ DC and not other DC types are particularly adept at cross-presenting antigens is unclear because the mechanisms involved in antigen transfer from endolysosomal compartments to the cytosol remains poorly characterised and controversial. In any case, there is consensus that degradation of antigen in the cytosol has a crucial role in cross-presentation. 5 The protease inhibitor serpinb9 (Sb9), previously called PI-9 in human or Spi6 in mouse, is a regulator of ...