Menu
MapConnectionsTopicsBulgariaThe Night (K-TRIO)Marie Skłodowska-CurieFor studentsFor teachersMethodologySurprise me
H2020Individual fellowship2019–2021

PI3K-in-tolerance · PI3K delta role in dendritic cell antigen processing and presentation to control gut tolerance

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2019-11-01 → 2021-11-14
EU contribution
€212,934
Participants
1
Scheme
MSCA-IF

Lines connect the coordinator with its partners.

Results in brief

PI3K delta role in dendritic cell antigen processing and presentation to control gut tolerance

Effective mammalian host defence against pathogenic microorganisms involve activation of dendritic cells (DCs) with potent priming ability to orchestrate adaptive T cell responses. Paradoxically within the intestine, the mammalian host encounters trillions of microbes and their components that alternatively stimulate DCs to promote immune tolerance to commensal bacteria. Aberrations in microbial surveillance or tolerance result in intestinal inflammation and inflammatory bowel disease (IBD) that affects the industrialised world. The mechanisms involved in colitis development and maintenance involve host and microbiota interplay, yet more studies regarding the molecular mechanisms of host gut immunity are required to uncover effective therapeutic strategies. Phosphatidylinositol-3-OH kinases (PI3Ks) control pattern recognition receptor (PRR) signaling and coordinate phagosome dynamics. The class I PI3K p110 delta (p110δ) isoform is predominantly expressed in the hematopoietic compartment and inborn errors of the mammalian p110δ PI3K leads to defects in antimicrobial immunity and colitis, yet little known how p110δ safeguards host immunity. In this project, we have utilised molecular immunology, biochemistry, and mouse genetics tools and uncovered akey role of p110δ PI3K in DCs that orchestrate priming and activation of antigen specific T cells, summarised as (1) the presentation of phagosomal antigens within the MHCI and MHCII that upon microbial recognition by PRRs (2) DC-intrinsic p110δ role in imprinting tolerogenic regulatory T cells in the gut and (3) characterised the molecular components under p110δ, coordinating antigen processing and presentation process in DC phagosomes to orchestrate peripheral T cell tolerance to intestinal microorganisms and immune homeostasis. Our study provides a strong rationale to therapeutically target PI3K signalling in DCs to parse out cellular and molecular interactions within the mammalian intestine.

Data: CORDIS, © European Union

Project objective

PI3Ks controls important biological processes immunity controlling vesicular trafficking and cell signaling events triggered by pathogen recognition receptors (PRRs). The engagement of PRRs leading to DC antigen processing and presentation (APP) is essential for the bridge between innate and adaptive immunity. Thus, DCs are crucial for resistance against pathogens, while concurrently maintaining tolerance to the commensal microbiota and environmental antigens. Crohn’s disease (CD)-like pathology has been documented in patients with chronic granulomatous disease (CGD), originating from mutations in genes encoding NADPH oxidase (NOX2) subunits or RAC2 GTPase. Both PRR-activated NOX2 and RAC2 are critical for inducing phagosomal reactive oxygen species (ROS) linked to APP processes in the DC. Thus, that dysregulated PRR signalling and NOX2 activity in the DC phagosome, may be key steps involved in some of the pathology observed in CD. The PRR family member NOD2 senses muramyl dipeptide in bacteria. NOD2 was the first susceptibility gene identified for CD and associated with tolerance mechanisms mediating intestinal homeostasis to gut microbiota. Recently, interactions between NOD2 and microbiome were shown to stimulate Treg activity at the mucosal sites. Bacteria-derived outer membrane vesicles (OMVs) from gut commensal Bacteriodes fragilis induce mucosal tolerance by DC-intrinsic activation of NOD2 and enabling DCs to induce IL10 production from Tregs. It is known that OMVs require NOX2-induced ROS to be released for APP and presented by MHCII to activate CD4 Tregs. Our preliminary data shows that mice inactivated in the kinase domain of PI3K delta spontaneously develop colitis in the presence of an intestinal opportunistic pathogens and show defects in antigen presentation in DCs in vitro. Based on these results, I propose to investigate the DC-intrinsic PI3K role in APP functions that control gut tolerance in this animal model of colitis.

Original text from CORDIS.

Participants

Links

Data: CORDIS, © European Union