Trends in Immunology
Volume 36, Issue 1, January 2015, Pages 21-29
Journal home page for Trends in Immunology

Review
Focus: mTOR in immunity
Intersection of mTOR and STAT signaling in immunity

https://doi.org/10.1016/j.it.2014.10.006Get rights and content

Highlights

  • Crucial roles for mTOR and STAT signaling pathways in the control of immune cell fate.

  • Emerging evidence for crosstalk between mTOR and STAT pathways in immune regulation.

  • Cooperation between these pathways enables optimal induction of immune responses.

Optimal regulation of immune networks is essential for the generation of effective immune responses, and defects in such networks can lead to immunodeficiency while uncontrolled responses can result in autoimmune disorders. mTOR and STAT signaling cascades are key regulators of the differentiation and function of cells of the immune system. Both pathways act as sensors and transducers of environmental stimuli, and recent evidence has revealed points of crosstalk between these pathways, highlighting synergistic regulation of immune cell differentiation and function. We review here the current understanding of mTOR and STAT interactions in T cells and innate immune cells, and discuss potential mechanisms underlying these events. We further outline models for the intersection of these pathways in the regulation of immunity and highlight important areas for future research.

Section snippets

mTOR and STAT signaling in the immune system

The mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription (STAT) signaling pathways have been identified as key regulators in the development, survival, and function of cells of the immune system, including CD8+ cytotoxic T (Tc) cells, CD4+ T helper (Th) cells, CD4+ T regulatory cells (Tregs), dendritic cells (DCs), and monocytes 1, 2. These pathways have been shown to play unique roles during innate and adaptive immunity, and deregulation of their activation

Coordinated functions of mTOR and STAT pathways in T cells

In past years, strong evidence has associated mTOR signaling with T cell activation and lineage specification, and with the development of T cell memory 22, 23. STAT proteins have been associated with T cell development, differentiation, and survival 24, 25, 26. Recent evidence suggests that STAT transcription factors transduce environmental stimuli in part by controlling activation of lineage-specific enhancers and, at the same time, suppressing enhancers associated with alternative cell fates

mTOR-dependent regulation of STAT activation in dendritic cells and macrophages

Monocytes and macrophages are important effectors and regulators of innate immunity, whereas dendritic cells (DCs) initiate and control adaptive immune responses [47]. There is accumulating evidence that mTOR and STAT3 signaling are required for proper development and function of DCs 48, 49, 50, 51, suggesting potential crosstalk between these pathways. Two independent studies 52, 53 demonstrated that selective mTORC1 inhibition using rapamycin inhibits IL-10 expression and STAT3

Regulation of STAT activation by mTORC2 complexes during engagement of the type I IFN receptor

There has been extensive evidence that STAT signaling pathways play key and essential roles in the generation of type I IFN responses 57, 58, 59. Recent studies have also provided evidence that mTORC2 activity is required for transcriptional regulation of IFN-stimulated genes (ISGs) 18, 60. In addition, mTORC1-mediated signaling events are essential for mRNA translation of ISGs 61, 62, suggesting cooperation between mTOR and STAT pathways for optimal expression of IFN-inducible proteins. Recent

Concluding remarks

In recent years there has been accumulating evidence that mTOR and STAT pathways are crucial for the control and generation of immune responses. Although the effectors of each pathway are required for expression of gene products that modulate key immune functions, there is also evidence that these pathways crossregulate each other (Box 4). The evidence for crosstalk between mTOR and JAK/STAT pathways lends support for the targeting of these two pathways as new treatment strategies for several

Acknowledgments

The research of L.C.P. is supported by grants CA77816, CA155566, CA161196, and CA121192 from the National Institutes of Health.

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