The MYCL and MXD1 transcription factors regulate the fitness of murine dendritic cells.

Abstract

We previously found that MYCL is required by a <i>Batf3</i>-dependent classical dendritic cell subset (cDC1) for optimal CD8 T cell priming, but the underlying mechanism has remained unclear. The MAX-binding proteins encompass a family of transcription factors with overlapping DNA-binding specificities, conferred by a C-terminal basic helix-loop-helix domain, which mediates heterodimerization. Thus, regulation of transcription by these factors is dependent on divergent N-terminal domains. The MYC family, including MYCL, has actions that are reciprocal to the MXD family, which is mediated through the recruitment of higher-order activator and repressor complexes, respectively. As potent proto-oncogenes, models of MYC family function have been largely derived from their activity at supraphysiological levels in tumor cell lines. MYC and MYCN have been studied extensively, but empirical analysis of MYCL function had been limited due to highly restricted, lineage-specific expression in vivo. Here we observed that <i>Mycl</i> is expressed in immature cDC1s but repressed on maturation, concomitant with <i>Mxd1</i> induction in mature cDC1s. We hypothesized that MYCL and MXD1 regulate a shared, but reciprocal, transcriptional program during cDC1 maturation. In agreement, immature cDC1s in <i>Mycl</i>^<i>-/-</i> -deficient mice exhibited reduced expression of genes that regulate core biosynthetic processes. Mature cDC1s from <i>Mxd1</i>^-/- mice exhibited impaired ability to inhibit the transcriptional signature otherwise supported by MYCL. The present study reveals LMYC and MXD1 as regulators of a transcriptional program that is modulated during the maturation of <i>Batf3</i>-dependent cDC1s.