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Distinct strengths of mTORC1 control T-cell memory via transcriptional FOXO1 and metabolic AMPKα1 pathways in linear cell differentiation and asymmetric cell division models

Cellular & Molecular Immunology volume 19, pages 1073–1076 (2022)Cite this article

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A Correction to this article was published on 25 January 2023

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The “linear cell differentiation (LCD)” or “signal strength” model was originally proposed by Sallusto’s group in 2000 and posits that strong and weak strengths of the aforementioned three signals control T-cell differentiation into short-lived TE and long-lived TM cells, respectively (Fig. 1B) [2]. Subsequent evidence has accumulated in support of this model, with distinct strengths of TCR or antigen (high and low affinities) and IL-2 (high and low doses) signals favoring TE and TM cell differentiation, respectively [4, 5]. Various transcription factors crucial to controlling T-cell phenotypes have been identified, with forkhead box-O-1 (FOXO1), FOXO1-regulated T-cell factor-1 (TCF1), inhibition of DNA-binding protein-3 (Id3) and Eomes favoring TM cell differentiation and T-bet and Id2 favoring TE cell differentiation (Fig. 1B) [1]. Adenosine monophosphate-activated protein kinase-α1 (AMPKα1) is a conserved energy sensor that plays central role in controlling cellular metabolism and survival [6]. AMPKα1 stimulates mitochondrial biogenesis and fatty acid oxidation (FAO) to support TM-cell differentiation by increasing the abundance of Unc-51-like autophagy-activating kinase-1 (ULK1), autophagy-related gene-7 (ATG7), proliferator-activated receptor-γ coactivator-1α (PGC1α) and aquaporin-9 (AQP9). In contrast, mammalian target of rapamycin complex-1 (mTORC1) regulates the expression of hypoxia-inducible factor-1α (HIF-1α) and cMyC, which in turn promote glycolytic metabolism crucial for TE cell development (Fig. 1B) [6]. However, despite concerted efforts to identify the contributions of key transcription factors and metabolic profiles to T-cell memory, the underlying molecular mechanism(s) controlling distinct T-cell differentiation programs has yet to be discovered.

mTORC1 is an evolutionarily conserved protein complex that senses the strengths of all three signals and plays important role in T-cell proliferation, metabolism, and differentiation [1]. In 2009, Ahmed’s group provided the first evidence that rapamycin (Rapa)-mediated inhibition of mTORC1 promotes CD8+ TM-cell formation [7]. This finding was further supported by evidence that Rapa induces T-cell memory via a FOXO1-dependent transcriptional switch from T-bet to Eomes [8]. However, the molecular mechanism underlying Rapa-promoted T-cell memory is largely unknown.

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Fig. 1

Change history

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Acknowledgements

This work was supported by a research grant (#PJT153314) from the Canadian Institute of Health Research (CIHR).

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Authors and Affiliations

  1. Cancer Research Cluster, Saskatchewan Cancer Agency, Saskatoon, SK, Canada

    Junqiong Huang & Jim Xiang

  2. Department of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada

    Junqiong Huang & Jim Xiang

  3. Department of Blood Transfusion, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China

    Junqiong Huang

  4. Department of Biochemistry, Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada

    Scot Leary

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Correspondence to Jim Xiang.

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The original online version of this article was revised: In the version of this article initially published, unintended typographical errors in the original version of Fig. 1B were made during manuscript preparation. The revised Fig. 1, including the correct Fig. 1B, is shown below.

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Huang, J., Leary, S. & Xiang, J. Distinct strengths of mTORC1 control T-cell memory via transcriptional FOXO1 and metabolic AMPKα1 pathways in linear cell differentiation and asymmetric cell division models. Cell Mol Immunol 19, 1073–1076 (2022). https://doi.org/10.1038/s41423-022-00879-w

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