L-Myc expression by dendritic cells is required for optimal T-cell priming

Abstract

The transcription factors c-Myc and N-Myc encoded by Myc and Mycn, respectively, regulate cellular growth1 and are required for embryonic development2,3. A third paralog, Mycl1, is dispensable for normal embryonic development but its normal biologic function has remained unclear4. To examine the in vivo function of Mycl1, we generated an inactivating Mycl1gfp allele that also reports Mycl1 expression. We found that Mycl1 was selectively expressed in dendritic cells (DCs) of the immune system and controlled by IRF8, and that during DC development, Mycl1 expression was initiated in the common DC progenitor5 (CDP) concurrent with reduction in c-Myc expression. Mature DCs lacked expression of c-Myc and N-Myc, but maintained L-Myc expression even in the presence of inflammatory signals, such as GM-CSF. All DC subsets developed in Mycl1-deficient mice, but several DC subsets, such as migratory CD103+ cDCs in the lung and liver, were significantly reduced at steady state. Importantly, loss of L-Myc by DCs caused a significant decrease in the in vivo T-cell priming during infection by Listeria monocytogenes and vesicular stomatitis virus. The replacement of c-Myc by L-Myc in immature DCs may provide for Myc transcriptional activity in the setting of inflammation that is required for optimal T-cell priming6.

Comparative analysis of the efficiency and specificity of myeloid-Cre deleting strains using ROSA-EYFP reporter mice

“…Until these mouse strains are compared side by side in same analysis, it will be hard to know for certain. Analysis of transcription factors distinguishing sub-populations of dendritic cells has suggested new targets for directing Cre expression to dendritic cell subsets, including Zbtb46 and MycL (Satpathy et al, 2012; Wumesh et al, 2014), and led to the development of newer Cre lines such as Clec9A(Dngr-1)-cre (Schraml et al, 2013). Other distinguishing genes may be identified from resources such as the Immunological Genome project (www.immgen.org) for use in defining populations of DCs (Miller et al, 2012) and tissue macrophages (Gautier et al, 2012) and leading to the development of new Cre strains.…”

Dendritic cell metabolism

“…There are three MYC paralogues: MYC, MYCN and MYCL. During DC development, MYC expression is downregulated as MYCL expression is turned on in cDC progenitors 25 . CD103 + cDCs fail to develop normally in the absence of MYCL and, although CD8α + cDCs do develop in MYCL-deficient mice, they are less capable of activating T cells during infections with Listeria monocytogenes or vesicular stomatitis virus, suggesting that they are unable to mature into efficient antigen-presenting cells 25 .…”

“…During DC development, MYC expression is downregulated as MYCL expression is turned on in cDC progenitors 25 . CD103 + cDCs fail to develop normally in the absence of MYCL and, although CD8α + cDCs do develop in MYCL-deficient mice, they are less capable of activating T cells during infections with Listeria monocytogenes or vesicular stomatitis virus, suggesting that they are unable to mature into efficient antigen-presenting cells 25 . Although the extent to which this reflects an important role of MYCL in DC metabolism is unclear at this point, it is intriguing that the ability of GM-CSF — which acts as a growth factor and signals through phosphoinositide 3-kinase (PI3K)–AKT and presumably mTORC1 — to promote CD8α + cDC survival ex vivo is substantially diminished in the absence of Mycl 25 .…”

“…CD103 + cDCs fail to develop normally in the absence of MYCL and, although CD8α + cDCs do develop in MYCL-deficient mice, they are less capable of activating T cells during infections with Listeria monocytogenes or vesicular stomatitis virus, suggesting that they are unable to mature into efficient antigen-presenting cells 25 . Although the extent to which this reflects an important role of MYCL in DC metabolism is unclear at this point, it is intriguing that the ability of GM-CSF — which acts as a growth factor and signals through phosphoinositide 3-kinase (PI3K)–AKT and presumably mTORC1 — to promote CD8α + cDC survival ex vivo is substantially diminished in the absence of Mycl 25 . Moreover, key metabolism genes, including complex I (NADH oxidase) of the ETC, are expressed to a lesser extent in CD8α + cDCs in the absence of Mycl , indicating that this gene has a role in the regulation of metabolic processes; this finding may reflect a broader role of MYC in mitochondrial biogenesis 26 .…”

Cutting Edge: ACVRL1 Signaling Augments CD8α+ Dendritic Cell Development

“…1I). IRF8 binding sites confirmed by ChIP analysis can also be seen as peaks upstream of the TSS in recently reported IRF8 ChIP-sequencing studies (22,23). IRF8 is recruited near the major TSS of Acvrl1 gene selectively in CD24 + cDCs (CD8a + DC equivalent population) but not in pDCs (Fig.…”