mTOR Links Environmental Signals to T Cell Fate Decisions

Abstract

T cell fate decisions play an integral role in maintaining the health of organisms under homeostatic and inflammatory conditions. The localized microenvironment in which developing and mature T cells reside provides signals that serve essential functions in shaping these fate decisions. These signals are derived from the immune compartment, including antigens, co-stimulation, and cytokines, and other factors, including growth factors and nutrients. The mechanistic target of rapamycin (mTOR), a vital sensor of signals within the immune microenvironment, is a central regulator of T cell biology. In this review, we discuss how various environmental cues tune mTOR activity in T cells, and summarize how mTOR integrates these signals to influence multiple aspects of T cell biology.

Keywords: T cells; Treg cells; iNKT cell; mTOR.

Figure 1

Select upstream regulators and downstream effectors of mTOR signaling. Multiple signaling pathways emanating from the TCR, co-stimulatory receptors, cytokines, and nutrients (amino acids) tune mTOR activation in T cells. In this figure, black circles represent phosphorylation events. Solid arrows indicate a direct, activating phosphorylation event mediated by an upstream kinase, while dashed arrows indicate an indirect, positive regulatory role for a protein in a particular pathway. Inhibitory phosphorylation events or control of pathway activation are indicated by solid or dashed flat-ended arrows, respectively.

Figure 2

mTOR is a critical regulator of thymocyte development. T cell progenitors first develop within the bone marrow and migrate to the thymus. Here, cells respond to multiple environmental stimuli and progress through CD4⁻CD8⁻ double negative (DN) stages 1–4 to the double positive (DP) stage. These DP thymocytes will then adopt different cellular fates in response to additional cues. Red arrows indicate where mTORC1 and/or mTORC2 control thymocyte fate decisions, where plus signs (+) represent positive regulation and minus signs (−) depict negative regulation.

Figure 3

mTOR signaling controls peripheral T cell fate decisions. In the peripheral tissues, T cell quiescence is controlled by low levels of mTORC1 signaling. Upon receiving antigen and co-stimulatory signals, T cells rapidly expand. In the presence of select cytokines, CD4⁺ T cells further differentiate into different effector CD4⁺ T cell lineages. CD8⁺ T cells will become effector T cells before becoming memory T cells. The roles mTORC1 and mTORC2 serve in various T cell states are indicated within the figure, with positive roles shown with plus (+) signs and negative roles indicated by minus (−) signs. Question marks (?) indicate pathways requiring further investigation.

Figure 4

T cell trafficking is linked to mTOR. mTORC1 and mTORC2 control T cell trafficking by regulating the expression and/or functional activation of multiple transcription factors. In this manner, mTOR signaling regulates trafficking into inflammatory sites, lymph nodes, and mucosal sites.