Transcriptional reprogramming of CD11b+Esam(hi) dendritic cell identity and function by loss of Runx3

Joseph Dicken; Alexander Mildner; Dena Leshkowitz; Ivo P Touw; Shay Hantisteanu; Steffen Jung; Yoram Groner

doi:10.1371/journal.pone.0077490

Transcriptional reprogramming of CD11b+Esam(hi) dendritic cell identity and function by loss of Runx3

PLoS One. 2013 Oct 15;8(10):e77490. doi: 10.1371/journal.pone.0077490. eCollection 2013.

Authors

Joseph Dicken¹, Alexander Mildner, Dena Leshkowitz, Ivo P Touw, Shay Hantisteanu, Steffen Jung, Yoram Groner

Affiliation

¹ Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel.

Abstract

Classical dendritic cells (cDC) are specialized antigen-presenting cells mediating immunity and tolerance. cDC cell-lineage decisions are largely controlled by transcriptional factor regulatory cascades. Using an in vivo cell-specific targeting of Runx3 at various stages of DC lineage development we show that Runx3 is required for cell-identity, homeostasis and function of splenic Esam(hi) DC. Ablation of Runx3 in DC progenitors led to a substantial decrease in splenic CD4(+)/CD11b(+) DC. Combined chromatin immunoprecipitation sequencing and gene expression analysis of purified DC-subsets revealed that Runx3 is a key gene expression regulator that facilitates specification and homeostasis of CD11b(+)Esam(hi) DC. Mechanistically, loss of Runx3 alters Esam(hi) DC gene expression to a signature characteristic of WT Esam(low) DC. This transcriptional reprogramming caused a cellular change that diminished phagocytosis and hampered Runx3(-/-) Esam(hi) DC capacity to prime CD4(+) T cells, attesting to the significant role of Runx3 in specifying Esam(hi) DC identity and function.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD11b Antigen / genetics*
CD11b Antigen / immunology
CD4 Antigens / genetics
CD4 Antigens / immunology
CD4-Positive T-Lymphocytes / cytology
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
Cell Adhesion Molecules / genetics*
Cell Adhesion Molecules / immunology
Cell Communication
Cell Differentiation
Cell Lineage / immunology
Cellular Reprogramming / genetics*
Cellular Reprogramming / immunology
Core Binding Factor Alpha 3 Subunit / deficiency
Core Binding Factor Alpha 3 Subunit / genetics*
Core Binding Factor Alpha 3 Subunit / immunology
Dendritic Cells / cytology
Dendritic Cells / immunology
Dendritic Cells / metabolism*
Gene Expression Profiling
Gene Expression Regulation
Immunoprecipitation
Mice
Mice, Transgenic
Phagocytosis
Sequence Analysis, DNA
Signal Transduction
Spleen / cytology
Spleen / immunology
Spleen / metabolism*
Transcription, Genetic*

Substances

CD11b Antigen
CD4 Antigens
Cell Adhesion Molecules
Core Binding Factor Alpha 3 Subunit
Esam protein, mouse
Runx3 protein, mouse

Grants and funding

This study was supported by grants from Israel Science Foundation individual grants to YG. URL: http://isf.org.il. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.