Trends in Immunology
ReviewFocus: mTOR in immunityIntersection of mTOR and STAT signaling in immunity
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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