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Differential IRF8 Requirement Defines Two Pathways of Dendritic Cell Development in Humans

56 Pages Posted: 5 Apr 2019 Publication Status: Published

See all articles by Urszula Cytlak

Urszula Cytlak

University of Newcastle - Institute of Cellular Medicine

Anastasia Resteu

University of Newcastle - Institute of Cellular Medicine

Sarah Pagan

University of Newcastle - Institute of Cellular Medicine

Kile Green

University of Newcastle - Institute of Cellular Medicine

Paul Milne

University of Newcastle - Institute of Cellular Medicine

Sheetal Maisuria

University of Leeds - Leeds Institute of Rheumatic and Musculoskeletal Medicine

David McDonald

University of Newcastle - Institute of Cellular Medicine

Gillian Hulme

University of Newcastle - Institute of Cellular Medicine

Andrew Filby

University of Newcastle - Institute of Cellular Medicine

Benjamin Carpenter

University of Oxford - Oxford Genomics Centre

Rachel Queen

University of Newcastle - Institute of Genetic Medicine

Sophie Hambleton

University of Newcastle - Institute of Cellular Medicine; Newcastle Hospitals NHS Foundation Trust - Great North Children’s Hospital

Rosie Hague

Royal Hospital for Children - Department of Paediatric Immunology and Infectious Diseases

Hana Lango Allen

University of Cambridge - Department of Haematology; University of Cambridge - NIHR BioResource

James Thaventhiran

University of Cambridge - Department of Medicine

Gina Doody

University of Leeds - Institute of Medical Research

Matthew Collin

University of Newcastle - Institute of Cellular Medicine; Newcastle upon Tyne Hospitals NHS Foundation Trust - Northern Centre for Cancer Care

Venetia Bigley

University of Newcastle - Institute of Cellular Medicine; Newcastle upon Tyne Hospitals NHS Foundation Trust - Northern Centre for Cancer Care

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Abstract

The formation of human dendritic cells (DC) is controlled by multiple hematopoietic transcription factors, including IRF8. Loss of IRF8 differentially affects plasmacytoid DC (pDC) and the classical DC lineages, cDC1 and cDC2. Additionally, cDC2 are heterogeneous, comprising DC-like DC2 and monocyte-like DC3. Using high dimensional analysis, in vitro differentiation, and an allelic series of human IRF8 deficiency, we show that CD1c+DC heterogeneity originates from two distinct pathways of DC development. The lymphoid-primed IRF8high pathway carries pDC, cDC1, and DC2 trajectories, while the common myeloid IRF8low pathway forms DC3 and monocytes. We trace distinct trajectories of cDC1, DC2 and DC3 through the GMP showing that AXL+SIGLEC6+ pre-DC map exclusively to the DC2 pathway. The preservation of human CD1c+DC in partial IRF8 deficiency is explained by the replacement of DC2 by an expanded DC3 population. These observations are congruent with lineage-primed models of hematopoiesis, illustrating new links between immune cell function and ontogeny.

Keywords: IRF8, dendritic cell, hematopoiesis, primary immunodeficiency, single cell RNA-sequencing, immunity

Suggested Citation

Cytlak, Urszula and Resteu, Anastasia and Pagan, Sarah and Green, Kile and Milne, Paul and Maisuria, Sheetal and McDonald, David and Hulme, Gillian and Filby, Andrew and Carpenter, Benjamin and Queen, Rachel and Hambleton, Sophie and Hague, Rosie and Allen, Hana Lango and Thaventhiran, James and Doody, Gina and Collin, Matthew and Bigley, Venetia, Differential IRF8 Requirement Defines Two Pathways of Dendritic Cell Development in Humans (April 3, 2019). Available at SSRN: https://ssrn.com/abstract=3365028 or http://dx.doi.org/10.2139/ssrn.3365028
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Urszula Cytlak

University of Newcastle - Institute of Cellular Medicine

Framlington Place
Newcastle upon Tyne, NE2 4HH
United Kingdom

Anastasia Resteu

University of Newcastle - Institute of Cellular Medicine

Framlington Place
Newcastle upon Tyne, NE2 4HH
United Kingdom

Sarah Pagan

University of Newcastle - Institute of Cellular Medicine

Framlington Place
Newcastle upon Tyne, NE2 4HH
United Kingdom

Kile Green

University of Newcastle - Institute of Cellular Medicine

Framlington Place
Newcastle upon Tyne, NE2 4HH
United Kingdom

Paul Milne

University of Newcastle - Institute of Cellular Medicine

Framlington Place
Newcastle upon Tyne, NE2 4HH
United Kingdom

Sheetal Maisuria

University of Leeds - Leeds Institute of Rheumatic and Musculoskeletal Medicine

United Kingdom

David McDonald

University of Newcastle - Institute of Cellular Medicine

Framlington Place
Newcastle upon Tyne, NE2 4HH
United Kingdom

Gillian Hulme

University of Newcastle - Institute of Cellular Medicine

Framlington Place
Newcastle upon Tyne, NE2 4HH
United Kingdom

Andrew Filby

University of Newcastle - Institute of Cellular Medicine

Framlington Place
Newcastle upon Tyne, NE2 4HH
United Kingdom

Benjamin Carpenter

University of Oxford - Oxford Genomics Centre

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Rachel Queen

University of Newcastle - Institute of Genetic Medicine

5 Barrack Road
Newcastle, NE1 7RU
United Kingdom

Sophie Hambleton

University of Newcastle - Institute of Cellular Medicine

Framlington Place
Newcastle upon Tyne, NE2 4HH
United Kingdom

Newcastle Hospitals NHS Foundation Trust - Great North Children’s Hospital

United Kingdom

Rosie Hague

Royal Hospital for Children - Department of Paediatric Immunology and Infectious Diseases

Glasgow
United Kingdom

Hana Lango Allen

University of Cambridge - Department of Haematology

Cambridge
United Kingdom

University of Cambridge - NIHR BioResource

United Kingdom

James Thaventhiran

University of Cambridge - Department of Medicine

MRC Laboratory of Molecular Biology
Francis Crick Avenue
Cambridge, CB2 0QH
United Kingdom

Gina Doody

University of Leeds - Institute of Medical Research

Leeds
United Kingdom

Matthew Collin

University of Newcastle - Institute of Cellular Medicine

Framlington Place
Newcastle upon Tyne, NE2 4HH
United Kingdom

Newcastle upon Tyne Hospitals NHS Foundation Trust - Northern Centre for Cancer Care

United Kingdom

Venetia Bigley (Contact Author)

University of Newcastle - Institute of Cellular Medicine ( email )

Framlington Place
Newcastle upon Tyne, NE2 4HH
United Kingdom

Newcastle upon Tyne Hospitals NHS Foundation Trust - Northern Centre for Cancer Care ( email )

United Kingdom

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