T cell activation is an energy-demanding process fueled by increased glucose consumption and accompanied by upregulation of the insulin receptor (INSR). In this article, we report that silencing the ...INSR in inducible knockdown rats impairs selective T cell functions but not thymocyte development. Glucose transport and glycolysis in activated CD4
T cells were compromised in the absence of the INSR, which was associated with alterations in intracellular signaling pathways. The observed metabolic defects coincided with reduced cytokine production, proliferation, and migration, as well as increased apoptosis of CD4
T cells. The cytotoxicity of CD8
T cells in response to alloantigens was also diminished under these conditions, whereas the frequency and suppressive capacity of regulatory T cells were unaffected. The observed impairments proved to be decisive in vivo because silencing of the INSR attenuated clinical symptoms in animal models of acute graft-versus-host disease and multiple sclerosis. Taken together, our results suggest that upregulation of the INSR on T cells following activation is required for efficient adaptive immunity.
Numerous Gram-negative pathogens use a Type III Secretion System (T3SS) to promote virulence by injecting effector proteins into targeted host cells, which subvert host cell processes. Expression of ...T3SS and the effectors is triggered upon host cell contact, but the underlying mechanism is poorly understood. Here, we report a novel strategy of Yersinia pseudotuberculosis in which this pathogen uses a secreted T3SS translocator protein (YopD) to control global RNA regulators. Secretion of the YopD translocator upon host cell contact increases the ratio of post-transcriptional regulator CsrA to its antagonistic small RNAs CsrB and CsrC and reduces the degradosome components PNPase and RNase E levels. This substantially elevates the amount of the common transcriptional activator (LcrF) of T3SS/Yop effector genes and triggers the synthesis of associated virulence-relevant traits. The observed hijacking of global riboregulators allows the pathogen to coordinate virulence factor expression and also readjusts its physiological response upon host cell contact.
T‐cell lymphopenia is a major risk factor for autoimmunity. Here we describe congenic Lewis (LEW) rats with a loss‐of‐function mutation in the Gimap5 gene, leading to a 92% reduction in peripheral ...T‐cell numbers. Gimap5‐deficient LEW rats developed eosinophilic autoimmune gastroenteritis accompanied by a 40‐fold increase in IgE serum levels. This phenotype was ameliorated by antibiotic treatment, indicating a critical role of the microbial flora in the development of inflammatory bowel disease. Interestingly, Gimap5‐deficient LEW rats showed strongly aggravated experimental autoimmune encephalomyelitis (EAE) after immunization with guinea pig myelin basic protein. This phenotype, however, persisted after antibiosis, confirming that the enhanced CNS autoimmune response in T‐cell lymphopenic Gimap5‐deficient LEW rats was unrelated to the composition of the microbial flora. Rather, it seems that it was caused by the 7‐fold increase in the percentage of activated T cells producing IL‐17 and IFN‐γ, and the skewed T‐cell receptor (TCR) repertoire, both of which were the result of T‐cell lymphopenia and not affected by antibiosis. This notion was supported by the observation that adoptive T‐cell transfer corrected the TCR repertoire and improved EAE. Collectively, our findings confirm a critical albeit differential role of T‐cell lymphopenia in the susceptibility to organ‐specific autoimmune responses.—Fischer, H. J., Witte, A.‐K., Walter, L., Gröne, H.‐J., van den Brandt, J., Reichardt, H. M. Distinct roles of T‐cell lymphopenia and the microbial flora for gastrointestinal and CNS autoimmunity. FASEB J. 30, 1724–1732 (2016). www.fasebj.org
Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that G3BPs reside at the ...cytoplasmic surface of lysosomes. They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress activation of the metabolic master regulator mechanistic target of rapamycin complex 1 (mTORC1) by amino acids and insulin. Like the TSC complex, G3BP1 deficiency elicits phenotypes related to mTORC1 hyperactivity. In the context of tumors, low G3BP1 levels enhance mTORC1-driven breast cancer cell motility and correlate with adverse outcomes in patients. Furthermore, G3bp1 inhibition in zebrafish disturbs neuronal development and function, leading to white matter heterotopia and neuronal hyperactivity. Thus, G3BPs are not only core components of SGs but also a key element of lysosomal TSC-mTORC1 signaling.
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•G3BPs act non-redundantly in the TSC-mTORC1 signaling axis•G3BPs reside at the lysosomal surface and inhibit mTORC1•The TSC complex requires G3BPs as its lysosomal tether•G3BP1 deficiency phenocopies TSC complex loss in cancer cells and neurons
Distinct from their contributions to stress granules, G3BPs regulate mTORC1 activity through spatial control of the TSC complex.
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