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Dendritic cell-derived IL-2 promotes apoptosis of terminally mature cells via a novel autocrine signaling pathway

ABSTRACT: Dendritic cells (DCs) are crucial for sensing pathogens and triggering immune response. GM-CSF myeloid dendritic cells (GM-DCs) secrete several cytokines including IL-2 upon activation by pathogen associated molecular pattern (PAMP) ligands. DC IL-2 has been shown to be important for innate and adaptive immune responses, however its importance in DC physiology has never been demonstrated. This is due to ambiguity in expression of the CD122 subunit of the IL-2 trimeric receptor complex crucial for signaling. We show here that autocrine IL-2 signaling is functional in GM-DCs in early time window of stimulation with PAMPs. IL-2 signaling selectively activates the JAK/STAT5 pathway by assembling holo-receptor complexs at the cell surface. Autocrine IL-2 signaling inhibits survival of PAMP matured GM-DCs which is crucial for maintaining immune tolerance and preventing autoimmunity. Our findings suggest immune regulation by a novel autocrine signaling pathway that can potentially be exploited in DC immunotherapy. Microarray technology was used to understand the role of IL-2 signaling in DC.

ORGANISM(S): Mus musculus

PROVIDER: GSE58120 | GEO | 2015/05/21

SECONDARY ACCESSION(S): PRJNA249063

REPOSITORIES: GEO

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Project description:Pro-inflammation triggered by microbial lipopolysaccharide (LPS) through Toll-like receptor (TLR) 4 in the presence of interferon (IFN)-g induces cytokine secretion in dendritic cells (DCs) tightly regulated by a defined differentiation program. This DC differentiation is characterized by a dynamic immune activating but also tolerance inducing phenotype associated with irreversible down-modulation of cytokines. CD40L on activated T cells further modifies DC differentiation. Using DNA micro arrays we showed down-regulated mRNA levels of TLR signaling molecules while CD40/CD40L signaling molecules were up-regulated at a time when LPS/IFN-g activated DCs have ceased cytokine expression. Accordingly we demonstrated that CD40/CD40L but not TLR4 or TLR3 signaling mediated by LPS or poly (cytidylic-inosinic) acid (poly I:C) and dsRNA re-established the capacity to secret interleukin (IL)-12 in LPS/IFN-g activated DCs, which have exhausted their potential for cytokine secretion. This resulting TH1 polarizing DC phenotype â which lacked accompanying secretion of the crucial immune suppressive IL-10 - enhanced activation of cytotoxic T lymphocytes (CTLs). We therefore conclude that immune modulation is restricted to a secondary T-cell mediated stimulus at an exhausted DC state which prevents an immune tolerant DC phenotype. These findings impacts on the rational design of TLR activated DC-based cancer vaccines for the induction of anti-tumoral CTL responses. Experiment Overall Design: Monocyte derived DCs were matured for 6 hours with 30 ng/ml lipopolysaccharide (LPS, E. coli strain O111:B4, Calbiochem, San Diego, CA) and 1.000 U/ml IFN-g (Imukin, Boehringer Ingelheim, Austria). RNA of DCs was isolated after 6, 12, 24, or 48 hours of maturation using the RNeasy kit (Qiagen, Hilden, Germany) and analyzed by the RZPD (German Resource Centre for Genome Research, Berlin) using the Affymetrix DNA micro array platform (U133 plus 2.0). DNA array data from different maturation-time experiments were compared to controls that were kept in culture for the same time without stimulation.

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Dendritic cell-derived IL-2 promotes apoptosis of terminally mature cells via a novel autocrine signaling pathway

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