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10.1126/sciimmunol.abg0791 http://scihub22266oqcxt.onion/10.1126/sciimmunol.abg0791 34145066!8422387!34145066     free     free     free Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Sci+Immunol 2021 ; 6 (60): ä Nephropedia Template TP {{tp|p=34145066|t=2021. Activation of mTORC1 at late endosomes misdirects T cell fate decision in older individuals |pdf=|usr=}}{{34145066}} gab.com Text Activation of mTORC1 at late endosomes misdirects T cell fate decision in older individuals JO: Sci Immunol http://www.kidney.de/pget.php?&tw=1&pmid=34145066 #FOAvip The nutrient-sensing mammalian target of rapamycin (mTOR) is integral to cell fate decisions after T cell activation. Sustained mTORC1 activity favors the generation of terminally differentiated effector T cells instead of follicular helper and memory T cells. This is particularly pertinent for T cell responses of older adults who have sustained mTORC1 activation despite dysfunctional lysosomes. Here, we show that lysosome-deficient T cells rely on late endosomes rather than lysosomes as an mTORC1 activation platform, where mTORC1 is activated by sensing cytosolic amino acids. T cells from older adults have an increased expression of the plasma membrane leucine transporter SLC7A5 to provide a cytosolic amino acid source. Hence, SLC7A5 and VPS39 deficiency (a member of the HOPS complex promoting early to late endosome conversion) substantially reduced mTORC1 activities in T cells from older but not young individuals. Late endosomal mTORC1 is independent of the negative-feedback loop involving mTORC1-induced inactivation of the transcription factor TFEB that controls expression of lysosomal genes. The resulting sustained mTORC1 activation impaired lysosome function and prevented lysosomal degradation of PD-1 in CD4(+) T cells from older adults, thereby inhibiting their proliferative responses. VPS39 silencing of human T cells improved their expansion to pertussis and to SARS-CoV-2 peptides in vitro. Furthermore, adoptive transfer of CD4(+) Vps39-deficient LCMV-specific SMARTA cells improved germinal center responses, CD8(+) memory T cell generation, and recall responses to infection. Thus, curtailing late endosomal mTORC1 activity is a promising strategy to enhance T cell immunity. Twit Text FOAVip Activation of mTORC1 at late endosomes misdirects T cell fate decision in older individuals ????Sci Immunol http://www.kidney.de/pget.php?&tw=1&pmid=34145066 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=34145066 #FOAvip English Wikipedia <ref>{{Cite pmid|34145066}}</ref> Activation of mTORC1 at late endosomes misdirects T cell fate decision in older individuals #MMPMID34145066 Jin J; Kim C; Xia Q; Gould TM; Cao W; Zhang H; Li X; Weiskopf D; Grifoni A; Sette A; Weyand CM; Goronzy JJ Sci Immunol 2021[Jun]; 6 (60): ä PMID34145066show ga The nutrient-sensing mammalian target of rapamycin (mTOR) is integral to cell fate decisions after T cell activation. Sustained mTORC1 activity favors the generation of terminally differentiated effector T cells instead of follicular helper and memory T cells. This is particularly pertinent for T cell responses of older adults who have sustained mTORC1 activation despite dysfunctional lysosomes. Here, we show that lysosome-deficient T cells rely on late endosomes rather than lysosomes as an mTORC1 activation platform, where mTORC1 is activated by sensing cytosolic amino acids. T cells from older adults have an increased expression of the plasma membrane leucine transporter SLC7A5 to provide a cytosolic amino acid source. Hence, SLC7A5 and VPS39 deficiency (a member of the HOPS complex promoting early to late endosome conversion) substantially reduced mTORC1 activities in T cells from older but not young individuals. Late endosomal mTORC1 is independent of the negative-feedback loop involving mTORC1-induced inactivation of the transcription factor TFEB that controls expression of lysosomal genes. The resulting sustained mTORC1 activation impaired lysosome function and prevented lysosomal degradation of PD-1 in CD4(+) T cells from older adults, thereby inhibiting their proliferative responses. VPS39 silencing of human T cells improved their expansion to pertussis and to SARS-CoV-2 peptides in vitro. Furthermore, adoptive transfer of CD4(+) Vps39-deficient LCMV-specific SMARTA cells improved germinal center responses, CD8(+) memory T cell generation, and recall responses to infection. Thus, curtailing late endosomal mTORC1 activity is a promising strategy to enhance T cell immunity. |Adoptive Transfer/methods[MESH] |Adult[MESH] |Aged[MESH] |Aged, 80 and over[MESH] |Animals[MESH] |Autophagy-Related Proteins/deficiency/genetics[MESH] |Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics/metabolism[MESH] |CD4-Positive T-Lymphocytes/*immunology[MESH] |CD8-Positive T-Lymphocytes/*immunology[MESH] |COVID-19/*immunology/virology[MESH] |Cells, Cultured[MESH] |Endosomes/*metabolism[MESH] |Female[MESH] |Forkhead Box Protein O1/deficiency/genetics[MESH] |Healthy Volunteers[MESH] |Humans[MESH] |Large Neutral Amino Acid-Transporter 1/metabolism[MESH] |Lysosomes/metabolism[MESH] |Male[MESH] |Mechanistic Target of Rapamycin Complex 1/*metabolism[MESH] |Mice[MESH] |Mice, Inbred C57BL[MESH] |Mice, Transgenic[MESH] |SARS-CoV-2/*metabolism[MESH] |Signal Transduction/*genetics/immunology[MESH] |Transfection[MESH] |Vesicular Transport Proteins/deficiency/genetics[MESH]Activation of mTORC1 at late endosomes misdirects T cell fate decision(epmc).pdf DeepDyve Pubget Overpricing