LAUSR

Following intense interest in the transcription factors that program differentiation and effector function of immune cells, the immunology community is now embracing the importance of cell metabolism in these processes. The mechanistic target of rapamycin, also known as the mammalian target of rapamycin (mTOR), composed of mTOR complexes 1 and 2 (mTORC1 and mTORC2), is a serine/threonine kinase that plays a key role in cell survival, proliferation, differentiation and migration, and is inhibited by rapamycin. mTOR integrates input from growth factors, amino acids, oxygen and energy levels with output of protein translation, but also of cell metabolism, as it promotes lipid synthesis and reduces fatty acid oxidation (FAO). Within T cells, mTORC1 promotes T helper (Th)1 and Th17 differentiation, but inhibits induced T regulatory (iTreg) cell differentiation and restrains T cell memory, whereas mTORC2 facilitates Th2 differentiation. The functional consequences of mTOR in dendritic cells (DCs) and antigen-presenting cells (APCs) in vivo are less well understood. To address this question, Sinclair and colleagues generated CD11c-Cre X Mtor fl/fl (MtorΔAPC) mice in which mTOR is genetically ablated in DCs and some macrophage subsets. These mice exhibited abnormal DC subset composition at steady state only in select tissues, and exaggerated Th17 responses in the inflamed lung, in a manner dependent on abnormal DC metabolism. DCs can be divided into CD8α+/CD103+ DCs and CD11b+ DCs. The growth factors needed for their homeostatic maintenance, Flt3L and granulocyte macrophage colony-stimulating factor (GMCSF), are known to activate mTOR. DC presentation of antigen to T cells is essential to initiate adaptive immune responses. Several groups have mapped the transcription factors within DCs that endow them with the ability to polarize T cells, such as DC-Irf8 for Th1, and DC-Irf4 for Th2 and Th17 differentiation. Sinclair and colleagues demonstrate that inhibition of mTOR signaling conditionally in DCs, independently of transcription factor expression, has a profound impact on T cell polarization in select tissues. At steady state, DC composition in the MtorΔAPC mice was minimally altered in most tissues, but was abnormal in skin and lung, with loss of Langerhans cells but not CD103+ cells in the skin, and loss of CD103+ cells and alveolar macrophages in the lung via increased cell death–dependent, but translation-independent, mechanisms. These data infer a role for tissue-specific factors in imprinting an mTORsensitive metabolic phenotype in APCs, and indeed, lung but not spleen APCs displayed a distinctive metabolic signature in the abSUMMARY AND ANALYSIS Watch LITERATURE