The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism

Abstract

In the two-signal model of T cell activation, the outcome of antigen recognition is determined by the integration of multiple cues in the immune microenvironment. mTOR is an evolutionarily conserved PI3-kinase family member that plays a central role in integrating environmental cues in the form of amino acids, energy, and growth factors. Recently, an increasingly important role for mTOR in directing T cell activation and differentiation has become apparent. Here we review recent findings demonstrating the ability of mTOR to interpret signals in the immune microenvironment and program the generation of CD4(+) effector versus regulatory T cells, the generation of CD8(+) effector versus memory cells, T cell trafficking, and T cell activation versus anergy. The key theme to emerge from these studies is that the central role of mTOR provides a direct link between T cell metabolism and function.

Figure 1. mTOR signaling for the immunologist

Based on the review of Laplante and Sabatini, this figure is designed to be a ready reference for upstream and downstream signaling as well as the components of mTORC1 and mTORC2. Details of mTORC1 and mTORC2 signaling pathways are described in the main text. Although the figure is not meant to be exhaustive, we try to emphasize the connections between CD28 and IL-2R signaling with signals derived from leucine, oxygen and energy. Note, blue lines indicate signals upstream of mTOR that ultimately lead to its activation. Purple lines depict upstream signals that lead to the inhibition of mTOR. Green lines show downstream mTOR signaling that promotes a particular function while red lines depict downstream inhibitory signals.

Figure 2. Linking metabolism and mTOR activity

Quiescence in T cells is an active state that is maintained by Slfn2, Foxos, TOB and KLF2. Naïve T cells are catabolic and have low levels of mTOR activity. Activation and effector generation for both CD4⁺ and CD8⁺ T cells results in tremendous metabolic demands and a switch from catabolism to anabolism (right). By necessity mTOR activity is high which not only supports this increase in metabolism but also promotes both CD8⁺ and CD4⁺ effector T cell generation. Alternatively, inhibition of mTOR in CD8⁺ T cells promotes the generation of memory cells. Such cells are characterized by low metabolic demands, low mTOR activity, and an increase in the Foxos, KLF2 and eomesodermin. Likewise, activation in the context of mTOR inhibition promotes the generation of regulatory T cells. These cells, which are less metabolically demanding than their effector counterparts, display decreased mTOR activity but increased Pim2 kinase activity.

Figure 3. Redefining Signal 2

Signal 1 refers to antigen recognition through the TCR and is characterized by the transcription of many genes. The outcome of this recognition is dictated by the net sum of environmental signals (Signal 2). We propose that mTOR acts to integrate all of these signals which in turn direct the outcome of T cell differentiation and activation.