Dendritic cell (DCs) develop from bone marrow progenitors that seed the periphery via the blood. As these progenitors differentiate in a tissue, they must adapt to the distinct metabolic environments of that tissue. A central question in biology is how do cells metabolically adapt to different tissue niches. To address this, we have developed a conditional knockout model (Cre/ LoxP) to specifically ablate a nutrient sensitive, glycosylation enzyme, O-GlcNAc transferase (OGT) in DCs. OGT dynamically regulates protein activity and function through the addition of N-acetylglucosamine (GlcNAc). We began by phenotyping DCs in multiple tissues (as different tissues feature radically different metabolic environments) and demonstrated that XCR1⁺ cDC1s, but not CD88^- CD26⁺ SIRPa⁺ cDC2s, critically require Ogt to develop specifically in the lungs, but not in other tissues. To determine where this ‘developmental block’ occurs in lung cDC1 development, we characterised their steady state developmental trajectory using flow cytometry and CITE-seq. Additionally, we have described that the cDC1 population in the lung is more heterogeneous than previously defined, identifying a novel progenitor population, and two terminally differentiated cDC1s with differential CD8 T cell priming capacities. 

It has been reported that lung cDC1s (migratory DC1s) are essential for generating efficacious CD8⁺ T cell responses against influenza. Surprisingly, Ogt KO mice were able to generate potent CD8⁺ T cell effector and memory responses to influenza, despite the lack of lung migDC1s. We assessed the antigen presentation capacity of each of the mig/resDC subsets and found that the migDC2s displayed vastly superior influenza MHC-I presentation capacity, fully compensating for the lack of migDC1s.

In conclusion we have highlighted a dual for OGT, first, in maintaining tissue specific development of cDC1s, and secondly, maintaining the functional divergence cDC1 and cDC2  in CD8 T cell immunity.