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Pore‐formation by adenylate cyclase toxoid activates dendritic cells to prime CD8+and CD4+T cells
- Source :
- Immunology and Cell Biology, Immunology and Cell Biology, Nature Publishing Group, 2016, 94 (4), pp.322-333. ⟨10.1038/icb.2015.87⟩, Immunology and Cell Biology, 2016, 94 (4), pp.322-333. ⟨10.1038/icb.2015.87⟩
- Publication Year :
- 2015
- Publisher :
- Wiley, 2015.
-
Abstract
- International audience; The adenylate cyclase toxin-hemolysin (CyaA) of Bordetella pertussis is a bi-functional leukotoxin. It penetrates myeloid phagocytes expressing the complement receptor 3 and delivers into their cytosol its N-terminal adenylate cyclase enzyme domain (~400 residues). In parallel, ~1300 residue-long RTX hemolysin moiety of CyaA forms cation-selective pores and permeabilizes target cell membrane for efflux of cytosolic potassium ions. The non-enzymatic CyaA-AC(-) toxoid, has repeatedly been successfully exploited as an antigen delivery tool for stimulation of adaptive T-cell immune responses. We show that the pore-forming activity confers on the CyaA-AC(-) toxoid a capacity to trigger Toll-like receptor and inflammasome signaling-independent maturation of CD11b-expressing dendritic cells (DC). The DC maturation-inducing potency of mutant toxoid variants in vitro reflected their specifically enhanced or reduced pore-forming activity and K(+) efflux. The toxoid-induced in vitro phenotypic maturation of DC involved the activity of mitogen activated protein kinases p38 and JNK and comprised increased expression of maturation markers, interleukin 6, chemokines KC and LIX and granulocyte-colony-stimulating factor secretion, prostaglandin E2 production and enhancement of chemotactic migration of DC. Moreover, i.v. injected toxoids induced maturation of splenic DC in function of their cell-permeabilizing capacity. Similarly, the capacity of DC to stimulate CD8(+) and CD4(+) T-cell responses in vitro and in vivo was dependent on the pore-forming activity of CyaA-AC(-). This reveals a novel self-adjuvanting capacity of the CyaA-AC(-) toxoid that is currently under clinical evaluation as a tool for delivery of immunotherapeutic anti-cancer CD8(+) T-cell vaccines into DC.
- Subjects :
- CD4-Positive T-Lymphocytes
0301 basic medicine
Cell Membrane Permeability
[SDV]Life Sciences [q-bio]
MESH: Adjuvants, Immunologic
CD8-Positive T-Lymphocytes
Lymphocyte Activation
p38 Mitogen-Activated Protein Kinases
MESH: Cancer Vaccines
Mice
Immunology and Allergy
MESH: Animals
MESH: Cell Membrane Permeability
Cells, Cultured
MESH: Cytokines
MESH: Pore Forming Cytotoxic Proteins
MESH: Dendritic Cells
Chemistry
Toxoid
MESH: CD4-Positive T-Lymphocytes
Cell Differentiation
Inflammasome
MESH: CD8-Positive T-Lymphocytes
Cell biology
Adenylate Cyclase Toxin
Cytokines
MESH: Protein Domains
[SDV.IMM]Life Sciences [q-bio]/Immunology
MESH: Cells, Cultured
medicine.drug
Pore Forming Cytotoxic Proteins
MESH: Cell Differentiation
Immunology
Adenylate kinase
Cancer Vaccines
Cyclase
03 medical and health sciences
Adjuvants, Immunologic
Protein Domains
MESH: Mice, Inbred C57BL
medicine
Animals
Secretion
MESH: Lymphocyte Activation
MESH: Mice
Ion Transport
Chemotaxis
Dendritic Cells
Cell Biology
cyaA
MESH: Adenylate Cyclase Toxin
Mice, Inbred C57BL
MESH: Ion Transport
MESH: p38 Mitogen-Activated Protein Kinases
030104 developmental biology
[SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology
Subjects
Details
- ISSN :
- 14401711 and 08189641
- Volume :
- 94
- Database :
- OpenAIRE
- Journal :
- Immunology & Cell Biology
- Accession number :
- edsair.doi.dedup.....5e7621bce15270defe1e4e243f36f86d