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Activation of mTORC1 at late endosomes misdirects T cell fate decision in older individuals.
Jin, Jun; Kim, Chulwoo; Xia, Qiong; Gould, Timothy M; Cao, Wenqiang; Zhang, Huimin; Li, Xuanying; Weiskopf, Daniela; Grifoni, Alba; Sette, Alessandro; Weyand, Cornelia M; Goronzy, Jorg J.
  • Jin J; Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA.
  • Kim C; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA, United States.
  • Xia Q; Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA.
  • Gould TM; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA, United States.
  • Cao W; Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA.
  • Zhang H; Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA.
  • Li X; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA, United States.
  • Weiskopf D; Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA.
  • Grifoni A; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA, United States.
  • Sette A; Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA.
  • Weyand CM; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA, United States.
  • Goronzy JJ; Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA.
Sci Immunol ; 6(60)2021 06 18.
Article in English | MEDLINE | ID: covidwho-1276879
ABSTRACT
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Endosomes / CD4-Positive T-Lymphocytes / Signal Transduction / CD8-Positive T-Lymphocytes / Mechanistic Target of Rapamycin Complex 1 / SARS-CoV-2 / COVID-19 Limits: Adult / Aged / Animals / Female / Humans / Male / Young adult Language: English Year: 2021 Document Type: Article Affiliation country: Sciimmunol.abg0791

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Endosomes / CD4-Positive T-Lymphocytes / Signal Transduction / CD8-Positive T-Lymphocytes / Mechanistic Target of Rapamycin Complex 1 / SARS-CoV-2 / COVID-19 Limits: Adult / Aged / Animals / Female / Humans / Male / Young adult Language: English Year: 2021 Document Type: Article Affiliation country: Sciimmunol.abg0791