Batf3 maintains autoactivation of Irf8 for commitment of a CD8α+ conventional DC clonogenic progenitor

Abstract

The transcription factors Batf3 and IRF8 are required for development of CD8α+ conventional dendritic cells (cDCs), but the basis for their actions was unclear. Here, we identify two novel Zbtb46+ progenitors that separately generate CD8α+ and CD4+ cDCs and arise directly from the common DC progenitor (CDP). Irf8 expression in the CDP depends on prior PU.1-dependent autoactivation, and specification of pre-CD8 DC progenitors requires IRF8 but not Batf3. However, upon pre-CD8 DC specification, Irf8 autoactivation becomes Batf3-dependent at a CD8α+ cDC-specific enhancer containing multiple AP1-IRF composite elements (AICEs) within the Irf8 superenhancer. CDPs from Batf3−/− mice that specify toward pre-CD8 DCs fail to complete CD8α+ cDC development due to decay of Irf8 autoactivation, and divert to the CD4+ cDC lineage.

Biallelic mutations in IRF8 impair human NK cell maturation and function

“…Gene dosage and mutation site-specific effects are commonly observed in transcriptions factors such as IRF8 that are regulated by superenhancer structures (40). As opposed to A201V/P224L, the K108E mutation is unable to activate IRF1-and PU.1-dependent transcription and, in the biallelic state, is associated with monocyte and DC deficiency and a very marked distortion of NK cell development in the ratio of CD56 bright to CD56 dim cells.…”

The transcription factor NR4A3 controls CD103+ dendritic cell migration

“…As NR4A1 and NR4A3 are also expressed in T cells, we compared NR4A1 and NR4A3 expression levels between MLN DC subsets and splenic CD4 + and CD8 + T cells. Although and pre-CD4 DCs, respectively (28). However, a specific function for NR4A3 in DCs in vivo has not been defined.…”

Cellular and molecular regulation of innate inflammatory responses

“…Conventional DCs are further classified into subgroups according to the expression of CD8ɑ that is regulated by a complex network of cytokines and transcriptional factors. [117][118][119][120][121] While CD8ɑ − classical dendritic cells (cDCs) primarily promote antigen-specific CD4 + T-cell activation via the MHC II pathway, CD8ɑ + cDCs characteristically mediate cross-presentation of exogenous antigens on MHC I molecules to cytotoxic T lymphocytes (CTL). Ligation of TLRs by microbial products in DCs rapidly induces the expression of inflammatory cytokines, chemokines and chemokine receptors, co-stimulatory molecules and MHC molecules, allowing procession and presentation of antigens to T cells, and therefore play essential roles in determining the activation and differentiation of T-cell subsets.…”