Regulation of T cells by mTOR: the known knowns and the known unknowns

Abstract

Mammalian/mechanistic target of rapamycin (mTOR) is emerging as an important integrator of environmental cues critical for the regulation of T cell activation, differentiation and function. Recent studies leveraging pharmacologic inhibition or T cell specific genetic deletion of signaling components in the mTOR pathway have provided important insights into the mechanisms involved, and have been informative in defining targets downstream of mTOR that promote immune regulation. However, these studies have also presented confusing and at times contradictory findings, highlighting the complexities involved in examining the mTOR pathway in distinct contexts. Here we review the current understanding of the roles of mTOR in T cell biology, highlighting emerging concepts and areas of investigation where the precise role of mTOR has yet to be fully discerned.

HIV-1 selectively targets gut-homing CCR6+CD4+ T cells via mTOR-dependent mechanisms

“…GSVA of transcripts uniquely modulated by ATRA in CCR6 + T cells identified pathways, including Akt and PI3K. The network representation of Akt/PI3K pathways, previously linked to Th17 lineage polarization (58-60) and reported to be upregulated in human lamina propria T cells (73), pointed to the upregulation of mTOR, a metabolic sensor involved in the regulation of numerous cellular functions via the formation of two different signaling complexes, mTORC1 and mTORC2 (74)(75)(76)(77). Considering the documented role of mTOR-mediated processes in the positive regulation of HIV replication (62,78), we proceeded to the validation of mTOR expression at protein and mRNA levels as well as functional validations in cells from the blood and/or colons of HIV-infected individuals receiving ART and uninfected study participants.…”

Unstable FoxP3 + T regulatory cells in NZW mice

“…The initial nodes of the response to IL-2 also seemed normal in NZW Tregs: comparable CD25 at the cell surface, no suggestive coding-region polymorphism in the NZW Il2ra locus, and comparable induction of STAT5 phosphorylation, ruling out defects in IL-2 sensing and/or immediate downstream signaling events. Thus, the defective response to low-dose IL-2 must occur at downstream steps of the signaling pathway and/or along STAT5-independent pathways triggered by IL-2, such as the Akt/ mTOR pathway, known to have a negative impact on Treg cells (48). A poor integrative response of IL-2-delivered signals in NZW Tregs may be connected to their less effective response to IL-33, despite higher expression of IL-33R.…”

Rapid Quantification of Mitogen-induced Blastogenesis in T Lymphocytes for Identifying Immunomodulatory Drugs

“…Interestingly, with increased PMA concentrations, the potency of CsA and FK506 dropped slightly, even though there was no additional cell diameter increase in the absence of these drugs (Figure 2A and 2B). Rapamycin, an immunosuppressant that inhibits mammalian target of rapamycin (mTOR) 29,30 , had a moderate but statistically significant effect ( Figure 3A, 3B and 3C). FTY720 is a sphingosine 1-phosphate receptor agonist that inhibits lymphocyte egress into circulation 31 and was recently found to inhibit TRPM7, a cation channel highly expressed in T lymphocytes 32 .…”