microRNA-mediated regulation of mTOR complex components facilitates discrimination between activation and anergy in CD4 T cells

Abstract

T cell receptor (TCR) signals can elicit full activation with acquisition of effector functions or a state of anergy. Here, we ask whether microRNAs affect the interpretation of TCR signaling. We find that Dicer-deficient CD4 T cells fail to correctly discriminate between activating and anergy-inducing stimuli and produce IL-2 in the absence of co-stimulation. Excess IL-2 production by Dicer-deficient CD4 T cells was sufficient to override anergy induction in WT T cells and to restore inducible Foxp3 expression in Il2-deficient CD4 T cells. Phosphorylation of Akt on S473 and of S6 ribosomal protein was increased and sustained in Dicer-deficient CD4 T cells, indicating elevated mTOR activity. The mTOR components Mtor and Rictor were posttranscriptionally deregulated, and the microRNAs Let-7 and miR-16 targeted the Mtor and Rictor mRNAs. Remarkably, returning Mtor and Rictor to normal levels by deleting one allele of Mtor and one allele of Rictor was sufficient to reduce Akt S473 phosphorylation and to reduce co-stimulation-independent IL-2 production in Dicer-deficient CD4 T cells. These results show that microRNAs regulate the expression of mTOR components in T cells, and that this regulation is critical for the modulation of mTOR activity. Hence, microRNAs contribute to the discrimination between T cell activation and anergy.

MiR‐15a/16 deficiency enhances anti‐tumor immunity of glioma‐infiltrating CD8+ T cells through targeting mTOR

“…Moreover, in our study, mTOR was identified as the direct target of miR-15/16 in CD81 T cells. Our results are in concordance with Antoine Marcais's study 18 in CD4 T cells, Dice deficiency confers increased sensitivity of CD4 T cells to TCR signals and the mTOR components were targeted by the microRNAs Let-7 and miR-16.…”

“…[13][14][15] Recent studies showed that miR-15a/16 also acted as an immune regulator in physiological and inflammatory conditions, impacting macrophage phagocytosis, 16 NK maturation 17 and T cell activation. 18 Therefore, we reasoned that targeting miR-15a/16 in the tumor microenvironment may attenuate glioma progression. To test this hypothesis, glioma expansion and survival time was examined in both wild-type (WT) and miR-15a/16 deficient C57BL/6 mice intracranially injected with the syngeneic glioma GL261 cells.…”

MicroRNAs: Roles in Regulating Neuroinflammation

“…In dendritic cells activated by LPS, let-7 inhibits Socs1 , which promotes dendritic cell maturation and their ability to drive T cell proliferation (Kim and others 2013; Zhang and others 2011). let-7 may also limit self-renewal of memory T cells (Almanza and others 2010), suppress CD4 + T cell activation, promote T cell anergy (Marcais and others 2014), and inhibit T h 17 cell differentiation (Zhang and others 2013). In the CNS, let-7 limits microglial activation (Cho and others 2015) and promotes differentiation of cultured glial progenitor cells into astrocytes (Shenoy and others 2015).…”

microRNA‐16 Is Downregulated During Insulin Resistance and Controls Skeletal Muscle Protein Accretion

“…Prior examination of miR-16 suggests regulation of Beclin dependent autophagy via inhibition of Bcl-2 in carcinomas [Pattingre et al, 2005;Xu et al, 2014;Huang et al, 2015a]. miR-16 has also been implicated in regulating protein synthesis through mTOR inhibition in both immune and cancer cells [Janaki Ramaiah et al, 2014;Marcais et al, 2014]. Janaki Ramaiah et al [2014] demonstrated direct binding of miR-16 to the 3 0 -UTR of the protein synthetic regulator Rps6kb1 (subunit of p70S6K1) and the down-regulatory effects observed at the protein level in multiple cancer cell lines.…”