MenTORing Immunity: mTOR Signaling in the Development and Function of Tissue-Resident Immune Cells

Abstract

Tissue-resident immune cells must balance survival in peripheral tissues with the capacity to respond rapidly upon infection or tissue damage, and in turn couple these responses with intrinsic metabolic control and conditions in the tissue microenvironment. The serine/threonine kinase mammalian/mechanistic target of rapamycin (mTOR) is a central integrator of extracellular and intracellular growth signals and cellular metabolism and plays important roles in both innate and adaptive immune responses. This review discusses the function of mTOR signaling in the differentiation and function of tissue-resident immune cells, with focus on the role of mTOR as a metabolic sensor and its impact on metabolic regulation in innate and adaptive immune cells. We also discuss the impact of metabolic constraints in tissues on immune homeostasis and disease, and how manipulating mTOR activity with drugs such as rapamycin can modulate immunity in these contexts.

Figure 1. mTORC1 and mTORC2 Mediate Separate but Overlapping Cellular Functions

In resting cells, or when extracellular amino acid concentrations are low, mTORC1 is dissociated from lysosomes and is inactive (left side of lysosome). When immune cells become activated, they express amino acid transporters to allow them to more efficiently acquire extracellular amino acids. This is coordinated with Akt-dependent signals that alleviate TSC2-dependent inhibition of Rheb, to allow recruitment of mTORC1 to lysosomes, where it becomes activated by Rheb (right side of lysosome). Active mTORC1 phosphorylates S6K and 4EBP, with the net result of increasing ribosomal biogenesis and the translation of mRNA subsets coding for a variety of proteins, but especially proteins involved in anabolic metabolic pathways and immune mediators. This enables activated cells to generate more metabolic intermediates for biosynthesis to support cell growth, proliferation, and effector functions. mTORC2, which can be directly activated by PI3K, also promotes metabolic reprogramming through Akt-mediated activation of hexokinase 2 (HK2) or inhibition of Foxo1. Downstream targets of mTORC2 such as SGK also play direct roles in Th cell differentiation and in cytoskeletal dynamics important for cell movement.

Figure 2. Asymmetric Lymphocyte Division Marked by Differential mTORC1 Segregation Can Dictate Cell Fate

During the first cellular division of a naive CD8⁺ T cell (green), emerging daughter cells assume distinct properties, marked initially by the segregation of mTORC1 into the daughter cell proximal to the antigen-presenting cell. Amino acid transporters (Slc7a5, Slc1a5) are also enriched in proximal cells (red), promoting increased mTORC1 activation and mTORC1-dependent c-Myc expression. Distal daughter cells (yellow) display less mTORC1 activity and increased AMPK activity. This imbalance of key metabolic regulators in the emerging cells leads to metabolic differences in proximal and distal daughter cells such that the former is more glycolytic and anabolic, whereas the latter is more catabolic. Divergent metabolic profiles, enforced by asymmetric mTORC1 distribution, have far-reaching consequences for daughter cell fate, with proximal cells destined to assume effector functions (short-lived Teff cells) and distal cells more likely to persist as long-lived memory cells. Surface markers and intracellular signaling molecules associated with each state are highlighted.

Figure 3. Amino Acid Sensing Is a Critical Control Point for Determining mTORC1 Activation, Metabolic Reprogramming, and Cellular Fate

Amino acid sufficiency, particularly branched chain amino acids (BCAAs) and arginine, is sensed by immune cells through a process coupled to mTORC1 activation. When mTORC1 is active, cellular metabolism is anabolic, and catabolic pathways are inhibited. This allows cellular growth, proliferation, and the development of effector functions to proceed. Amino acid limitation, due to low supply in the microenvironment or consumption by other immune cell types (M2 alternatively activated macrophages, MDSCs, or Treg cells), reduces mTORC1 activation and prevents metabolic reprogramming to support cellular activation. Expression by regulatory immune cells of enzymes that break down amino acids is a primary immune system intrinsic mechanism through which effector immune cell activation is regulated. Other events, such as infection or cancer, that lead to changes in amino acid availability, can effectively limit immune cell activation through the same pathway.