Orchestration of the Th2 response by dendritic cells
Lead Research Organisation:
University of Edinburgh
Department Name: Sch of Biological Sciences
Abstract
Key questions remain to be answered as to the relative contribution that specific components of the immune system make in shaping the nature of the developing immune response. Dendritic cells (DC) represent a highly specialised type of immune cell that play a decisive role in orchestration of this process. Such direction is critical, since the consequences of mounting an inappropriate immune response can be extremely damaging. However, in contrast to increasing awareness of the mechanisms by which pathogens such as bacteria or viruses activate DC, little is known about how they respond to more complex organisms. Schistosome worms are complex multicellular parasites that cause chronic disease in millions of people and the distinctive type of immune response that they induce is intimately involved in the development of many of the symptoms that accompany infection. The goal of our studies is to identify the fine detail of the mechanisms by which DC are able to direct the immune response to schistosomes and other pathogens that induce a similar type of reaction. Once we have this information, it will enable us to design novel drugs and vaccines against any condition in which the immune response is ‘unbalanced‘.
Technical Summary
Dendritic cells (DC) are the orchestrators of the immune response, able to assess the nature and context of encountered pathogens and to direct T cells appropriately. DC play a decisive role in activation, polarisation, and even regulation of the immune system. While there is an increasing understanding of how they carry out this role when they respond to pathogens such as bacteria, protozoa, or viruses, much less is known about how DC are activated and function in response to metazoan pathogens.
Building upon the foundation I have established during my MRC Career Development Fellowship, I intend to address some outstanding fundamental questions about T cell response induction and modulation by DC, focussing on the Th2 response to the parasitic trematode Schistosoma mansoni. Specifically: 1) what are the mechanisms of Th2 induction by DC? 2) what is the impact of the local environment on DC activation in a Th2 setting? 3) how do DC multitask in the face of stimulation by diverse pathogens? 4) what is the impact of DC depletion on Th2 development in vivo? 5) what is the functionality of Th2 cells induced by DC?
We will address these defined questions using a combination of in vivo and in vitro model systems, and during active murine infection: We will identify core mechanisms utilised by DC to direct T cell polarisation, and address the influence of epigenetics on this process using ChIP and Solexa sequencing; We will determine the impact of the tissue environment on DC activation and function in response to pathogens; We will gain a clear picture of the behaviour of DC and differently polarised effector T cells in single and co-infection settings using state-of-the-art confocal and multi-photon microscopy; We will identify at which stage DC are integral for Th2 induction and development in vivo using CD11c-DTR transgenic mice, and provide new insight into the heterogeneity and functionality of DC-driven effector Th2 cells with the aid of S. mansoni-specific TCR transgenic mice.
In addition to providing novel information about multiple facets of basic DC biology, this approach will provide a platform for rational design of vaccination and immunotherapy strategies.
Building upon the foundation I have established during my MRC Career Development Fellowship, I intend to address some outstanding fundamental questions about T cell response induction and modulation by DC, focussing on the Th2 response to the parasitic trematode Schistosoma mansoni. Specifically: 1) what are the mechanisms of Th2 induction by DC? 2) what is the impact of the local environment on DC activation in a Th2 setting? 3) how do DC multitask in the face of stimulation by diverse pathogens? 4) what is the impact of DC depletion on Th2 development in vivo? 5) what is the functionality of Th2 cells induced by DC?
We will address these defined questions using a combination of in vivo and in vitro model systems, and during active murine infection: We will identify core mechanisms utilised by DC to direct T cell polarisation, and address the influence of epigenetics on this process using ChIP and Solexa sequencing; We will determine the impact of the tissue environment on DC activation and function in response to pathogens; We will gain a clear picture of the behaviour of DC and differently polarised effector T cells in single and co-infection settings using state-of-the-art confocal and multi-photon microscopy; We will identify at which stage DC are integral for Th2 induction and development in vivo using CD11c-DTR transgenic mice, and provide new insight into the heterogeneity and functionality of DC-driven effector Th2 cells with the aid of S. mansoni-specific TCR transgenic mice.
In addition to providing novel information about multiple facets of basic DC biology, this approach will provide a platform for rational design of vaccination and immunotherapy strategies.
People |
ORCID iD |
| Andrew MacDonald (Principal Investigator / Fellow) |
Publications
Robson NC
(2014)
Optimal effector functions in human natural killer cells rely upon autocrine bone morphogenetic protein signaling.
in Cancer research
Redpath SA
(2013)
ICOS controls Foxp3(+) regulatory T-cell expansion, maintenance and IL-10 production during helminth infection.
in European journal of immunology
Obieglo K
(2019)
Type I interferons provide additive signals for murine regulatory B cell induction by Schistosoma mansoni eggs.
in European journal of immunology
Deaton AM
(2014)
A unique DNA methylation signature defines a population of IFN-?/IL-4 double-positive T cells during helminth infection.
in European journal of immunology
Jones GR
(2020)
The Methyl-CpG-Binding Protein Mbd2 Regulates Susceptibility to Experimental Colitis via Control of CD11c+ Cells and Colonic Epithelium.
in Frontiers in immunology
Costain A
(2022)
Dynamics of Host Immune Response Development During Schistosoma mansoni Infection
in Frontiers in Immunology
Besusso D
(2015)
1,25-Dihydroxyvitamin D3-Conditioned CD11c+ Dendritic Cells are Effective Initiators of CNS Autoimmune Disease.
in Frontiers in immunology
Jones GR
(2018)
Dynamics of Colon Monocyte and Macrophage Activation During Colitis.
in Frontiers in immunology
Mylonas KJ
(2013)
Alternative activation of macrophages by filarial nematodes is MyD88-independent.
in Immunobiology
Webb LM
(2021)
Plasmacytoid Dendritic Cells Facilitate Th Cell Cytokine Responses throughout Schistosoma mansoni Infection.
in ImmunoHorizons
Lundie R
(2016)
A central role for hepatic conventional dendritic cells in supporting Th2 responses during helminth infection
in Immunology & Cell Biology
Redpath SA
(2015)
Schistosoma mansoni Larvae Do Not Expand or Activate Foxp3+ Regulatory T Cells during Their Migratory Phase.
in Infection and immunity
Smith KA
(2012)
Type 2 innate immunity in helminth infection is induced redundantly and acts autonomously following CD11c(+) cell depletion.
in Infection and immunity
Casaravilla C
(2014)
Unconventional maturation of dendritic cells induced by particles from the laminated layer of larval Echinococcus granulosus.
in Infection and immunity
Jones LH
(2015)
Modulation of dendritic cell alternative activation and function by the vitamin A metabolite retinoic acid.
in International immunology
Perona-Wright G
(2012)
Concurrent bacterial stimulation alters the function of helminth-activated dendritic cells, resulting in IL-17 induction.
in Journal of immunology (Baltimore, Md. : 1950)
Smith KA
(2011)
Chronic helminth infection promotes immune regulation in vivo through dominance of CD11cloCD103- dendritic cells.
in Journal of immunology (Baltimore, Md. : 1950)
Reynolds LA
(2014)
MyD88 signaling inhibits protective immunity to the gastrointestinal helminth parasite Heligmosomoides polygyrus.
in Journal of immunology (Baltimore, Md. : 1950)
Van Der Werf N
(2011)
Th2 responses to helminth parasites can be therapeutically enhanced by, but are not dependent upon, GITR-GITR ligand costimulation in vivo.
in Journal of immunology (Baltimore, Md. : 1950)
Sibilano R
(2011)
Technical advance: soluble OX40 molecule mimics regulatory T cell modulatory activity on FceRI-dependent mast cell degranulation.
in Journal of leukocyte biology
Mellanby RJ
(2012)
TLR-4 ligation of dendritic cells is sufficient to drive pathogenic T cell function in experimental autoimmune encephalomyelitis.
in Journal of neuroinflammation
Ferret-Bernard S
(2012)
Plasma membrane proteomes of differentially matured dendritic cells identified by LC-MS/MS combined with iTRAQ labelling.
in Journal of proteomics
Morrison VL
(2014)
Loss of beta2-integrin-mediated cytoskeletal linkage reprogrammes dendritic cells to a mature migratory phenotype.
in Nature communications
Cook PC
(2015)
A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells.
in Nature communications
Hoy AM
(2014)
Parasite-derived microRNAs in host serum as novel biomarkers of helminth infection.
in PLoS neglected tropical diseases
Cook PC
(2012)
Alternatively activated dendritic cells regulate CD4+ T-cell polarization in vitro and in vivo.
in Proceedings of the National Academy of Sciences of the United States of America
Jenkins SJ
(2011)
Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation.
in Science (New York, N.Y.)
Webb LM
(2017)
Type I interferon is required for T helper (Th) 2 induction by dendritic cells.
in The EMBO journal
Rigby RE
(2014)
RNA:DNA hybrids are a novel molecular pattern sensed by TLR9.
in The EMBO journal
McFarlane AJ
(2017)
Enteric helminth-induced type I interferon signaling protects against pulmonary virus infection through interaction with the microbiota.
in The Journal of allergy and clinical immunology
Phythian-Adams AT
(2010)
CD11c depletion severely disrupts Th2 induction and development in vivo.
in The Journal of experimental medicine
| Description | Tolerogenic dendritic cells and Echinococcus |
| Organisation | University of the Republic |
| Department | Sectoral Commission for Scientific Research (CSIC) |
| Country | Spain |
| Sector | Academic/University |
| PI Contribution | Provision of advice and technical training of staff from Uruguay spending time in the lab |
| Collaborator Contribution | Development of a new area of research for my lab, and collaboration with a South American University |
| Impact | Successful Wellcome Trust Collaborative Project grant funding, as a co-applicant, to commence Feb 2011 |
| Start Year | 2010 |
| Description | Press interviews on CD11c depletion |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | Press release about a publication from the lab, which resulted in a live interview on Radio Scotland, coverage on STV, many online articles (eg BBC website, STV online etc), and published in Daily Express, Telegraph, Herald, Scotsman, Courier and Advertiser, Press and Journal and the Metro. Increased email contact from the public and other media outlets |
| Year(s) Of Engagement Activity | 2010 |
| Description | Press interviews on alternatively activated dendritic cells |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | Press release about a publication from the lab, which resulted in a live interview on on STV, many online articles, and published articles in the press in the Herald and front page of the Scottish Daily Mail. Increased email requests etc. about this research. |
| Year(s) Of Engagement Activity | 2012 |
| Description | Primary School visit |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Type Of Presentation | Workshop Facilitator |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | Approx 30 primary 6 pupils from a local school visited the department for 2 hours. In that time the children visited the Natural History Collection and also took part in an interactive lab-based workshop on Classification and Fossils. Enthusiastic feedback letters from all the pupils, and very positive feedback from their teachers. |
| Year(s) Of Engagement Activity | 2012 |