Expression of the Serpin Serine Protease Inhibitor 6 Protects Dendritic Cells from Cytotoxic T Lymphocyte–Induced Apoptosis

Abstract

Dendritic cells (DCs) play a central role in the immune system as they drive activation of T lymphocytes by cognate interactions. However, as DCs express high levels of major histocompatibility complex class I, this intimate contact may also result in elimination of DCs by activated cytotoxic T lymphocytes (CTLs) and thereby limit induction of immunity. We show here that immature DCs are indeed susceptible to CTL-induced killing, but become resistant upon maturation with anti-CD40 or lipopolysaccharide. Protection is achieved by expression of serine protease inhibitor (SPI)-6, a member of the serpin family that specifically inactivates granzyme B and thereby blocks CTL-induced apoptosis. Anti-CD40 and LPS-induced SPI-6 expression is sustained for long periods of time, suggesting a role for SPI-6 in the longevity of DCs. Importantly, T helper 1 cells, which mature DCs and boost CTL immunity, induce SPI-6 expression and subsequent DC resistance. In contrast, T helper 2 cells neither induce SPI-6 nor convey protection, despite the fact that they trigger DC maturation with comparable efficiency. Our data identify SPI-6 as a novel marker for DC function, which protects DCs against CTL-induced apoptosis.

CD40L‐expressing CD8 T cells prime CD8α+ DC for IL‐12p70 production

“…We did not observe significant killing of DC in our system, although the activated CD8 T cells exhibited increased ability to lyse peptide-pulsed EL4 targets (data not shown). This might be because CD40 and LPS stimulation protects DC from killing by CTL [55].…”

“…We did not observe significant killing of DC in our system, although the activated CD8 T cells exhibited increased ability to lyse peptide-pulsed EL4 targets (data not shown). This might be because CD40 and LPS stimulation protects DC from killing by CTL [55].The ability of CD8 T cells to prime DC for IL-12p70 may explain several in vivo observations made by other groups, e.g. how Similarly, the depletion of CD8 T cells during DNA vaccination is associated with a marked decrease in IFN-c-producing CD4 T cells [9].…”

Enhancement of suicidal DNA vaccine potency by delaying suicidal DNA-induced cell death

“…One strategy to further improve safety is to use molecules that have antiapoptotic function with a reduced concern for oncogenicity, such as TRANCE, 26 CD40 ligand, 27 IL-12, 28 IL-15, 29 and serine protease inhibitor 6. 30 Among these molecules, CD40 ligand, 31 IL-12, 32 and IL-15 33 have been tested for their ability to enhance conventional naked DNA vaccine potency. Thus, it would be interest- BCL-xL enhances suicidal DNA vaccine potency TW Kim et al ing to evaluate the role these apoptosis inhibitors play in enhancing the antigen-specific immune responses to suicidal DNA vaccines.…”

Recombinant E. coli efficiently delivers antigen and maturation signals to human dendritic cells: Presentation of MART1 to CD8+ T cells

“…In order to determine whether this phenomenon was restricted to OVA and murine APC/T-cell interactions, we investigated whether E. coli/LLO could be used to deliver the MART1 antigen to the MHC class I processing pathways of human DCs. Full-length 357 bp MART1 cDNA, containing the MART1 [27][28][29][30][31][32][33][34][35] HLA-A2-restricted epitope, was cloned into the pCRT7/CT-TOPO inducible expression vector. Inducible expression of MART1 protein was achieved in both native E. coli and E. coli/LLO (Fig.…”

“…As a consequence of the interaction with bacteria, human DCs undergo marked phenotypic and functional maturation. Furthermore, we show that fixed E. coli/ LLO expressing the well-characterised human melanoma antigen, MART1, 20,21 efficiently deliver the HLA-A2-restricted MART1 [27][28][29][30][31][32][33][34][35] epitope for processing and presentation on human MoDCs, suggesting the potential of this system as a novel strategy for human tumour immunotherapy.…”