Investigating the effects of mTORC1 signaling in vivo via deletion of the mTORC1 component raptor, Pelgrom and Patente et al. showed that mTORC1 regulated metabolism in an APC subset-specific manner, was required for effective cross-presentation by and maturation of cDC1s, and limited Langerhans cell activation. However, CD8+ T cell priming and IFNγ production in response to immunization were increased with loss of mTORC1, likely due to an accumulation of immunogenic EpCAM+ cDC1 subpopulation, which showed increased physical interactions with CD8+ T cells. These results point to mTORC as a potential target for immunotherapy.
Contributed by Lauren Hitchings
ABSTRACT: How mechanistic target of rapamycin complex 1 (mTORC1), a key regulator of cellular metabolism, affects dendritic cell (DC) metabolism and T cell-priming capacity has primarily been investigated in vitro, but how mTORC1 regulates this in vivo remains poorly defined. Here, using mice deficient for mTORC1 component raptor in DCs, we find that loss of mTORC1 negatively affects glycolytic and fatty acid metabolism and maturation of conventional DCs, particularly cDC1s. Nonetheless, antigen-specific CD8(+) T cell responses to infection are not compromised and are even enhanced following skin immunization. This is associated with increased activation of Langerhans cells and a subpopulation of EpCAM-expressing cDC1s, of which the latter show an increased physical interaction with CD8(+) T cells in situ. Together, this work reveals that mTORC1 limits CD8(+) T cell priming in vivo by differentially orchestrating the metabolism and immunogenicity of distinct antigen-presenting cell subsets, which may have implications for clinical use of mTOR inhibitors.
Author Info: (1) Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands. (2) Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands
Author Info: (1) Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands. (2) Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands. (3) Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands. (4) Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands. (5) Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands. (6) Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands. (7) Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands. (8) Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands. (9) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (10) Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: b.everts@lumc.nl.
