Research ArticleT CELLS

Activation of mTORC1 at late endosomes misdirects T cell fate decision in older individuals

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Science Immunology  18 Jun 2021:
Vol. 6, Issue 60, eabg0791
DOI: 10.1126/sciimmunol.abg0791

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Rewiring aged T cells

Age-associated decline in T cell function contributes to impaired immune responses to infection and vaccination. Effector versus memory T cell differentiation is controlled in part by signaling and metabolic reprogramming mediated by mechanistic target of rapamycin complex 1 (mTORC1), which is typically activated at amino acid–producing lysosomes. Jin et al. demonstrate that in naïve CD4+ T cells from older individuals, mTORC1 activation instead occurs at late endosomes and depends on the amino acid transporter SLC7A5. Late endosomal mTORC1 impaired T cell lysosomal function, reducing degradation of PD-1 and proliferative responses. Silencing VPS39, a gene that promotes late endosome formation, could increase proliferation of aged human T cells and memory responses of lysosome-defective T cells in LCMV-infected mice, demonstrating that targeting late endosomal mTORC1 activity may improve T cell function.

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