Transcriptional Reprogramming of CD11b+Esamhi Dendritic Cell Identity and Function by Loss of Runx3

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 Esamhi 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+Esamhi DC. Mechanistically, loss of Runx3 alters Esamhi DC gene expression to a signature characteristic of WT Esamlow DC. This transcriptional reprogramming caused a cellular change that diminished phagocytosis and hampered Runx3-/- Esamhi DC capacity to prime CD4+ T cells, attesting to the significant role of Runx3 in specifying Esamhi DC identity and function.

ERAP1/ERAP2 and RUNX3 polymorphisms are not associated with ankylosing spondylitis susceptibility in Chinese Han

“…Differentiation and function of CD8 + T cells, NK cells and dendritic cells are controlled partially by RUNX3 14, 15, 51. RUNX3 gene polymorphism, however, did not increase the risk of AS susceptibility in Chinese Han.…”

Runx3 at the interface of immunity, inflammation and cancer

“…It is thus possible that certain GIT and other inflammatory diseases are associated with particular RUNX3 SNPs, which might affect RUNX3 functions in leukocytes, such as CD8 + T cells, NK and DCs, all of which display distinct phenotypes when Runx3 is absent [11,13,139,140]. Significantly, many of the genes reported to be associated with increased risk for inflammatory GIT diseases, including celiac [141], Crohn's [142], UC [143] and inflammatory bowel disease (IBD) [144], were identified as Runx3 targets in CD8 + T, NK and/or DCs [11,139,140] (Table 6). The Runx3 targets Ets1, Ube2e3 and Zmiz1 are also susceptibility genes for psoriasis [132] (Table 6).…”

Carcinogen-Induced Skin Tumor Development Requires Leukocytic Expression of the Transcription Factor Runx3

“…Analysis revealed intense expression of Runx3/GFP in resident T cells and CD11b þ DCs (Fig. 1B), two well-established Runx3-expressing cell lineages (16,19,21,23). Similar epidermal analysis identified Runx3 expression in subsets of steady-state LCs and DETCs (Fig.…”

“…When lost, the development of TGFb-dependent epidermal Langerhans cells (LC) is abrogated, whereas dermal DCs (dDC) seem unaffected (18,19). Runx3 germline inactivation enhanced lung DC maturation, resulting in hypermature/-active alveolar DCs (19,20) and reprogrammed gene expression of CD11b þ Esam high splenic DCs (21). Despite these profound immune anomalies, in vivo studies of wound closure, contact hypersensitivity, and epidermal apoptosis were unaltered in skins of Runx3-null mice (18).…”