Enforcing mTORC1 activity in therapeutic CD4+ T cells promotes persistence but eventual immune exhaustion

Sillito F, Armbrecht E, O'Neill AT, McIntyre A, Nyatondo M, Holler A, Callender LA, Henson SM, Stauss H, Chakraverty R · 2026 · Journal of Immunology · Atlas ID SIL2026

What this study shows

Enforced RHEB overexpression (mTORC1 hyperactivation) in therapeutic CD4+ T cells boosts initial proliferation/persistence after adoptive transfer, but drives cells toward an exhausted phenotype (co-inhibitory receptors, impaired re-proliferation on rechallenge) -- a double-edged sword for CAR/TCR-T cell engineering, distinct from the CD8 response to the same manipulation.

Abstract

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There is substantial interest in developing novel engineering strategies to promote the sustained metabolic fitness of therapeutic T cells. We previously showed that overexpression of RAS homologue enriched in brain (RHEB), a positive regulator of mammalian target of rapamycin complex 1 (mTORC1), promotes aerobic glycolysis and increases the anti-tumor functions of effector CD8+ T cells. To address whether these effects are conserved in CD4+ T cells, we have now examined how enforced activation of mTORC1 activity affects CD4+ T cell differentiation and function.

Read the full abstract on PubMed →

At a glance

Evidence type	A Animal model Marked A because it is an animal intervention or observation study measuring an organismal outcome (model: Mouse CD4+ T cells, adoptive transfer tumor model); the code names the system studied -- animal work can be rigorous and still not be human data.
Study type	4 - Animal Study
Model system	Mouse CD4+ T cells, adoptive transfer tumor model
Journal	Journal of Immunology
Year	2026
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1093/jimmun/vkag206 · PMID 42566506

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

Intervention	Retroviral Rheb overexpression in CD4+ T cells, adoptive transfer
Target	Rheb / mTORC1
Model	Mouse CD4+ T cells (in vitro and adoptive transfer tumour model)
Effect	Enforced mTORC1 activity raised CD4+ T cell activation, metabolism and persistence but pushed persisting cells toward exhaustion and reduced tumour clearance.

In the Atlas

Cite this paper

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Sillito, F., Armbrecht, E., O'Neill, A. T., McIntyre, A., Nyatondo, M., Holler, A., Callender, L. A., Henson, S. M., Stauss, H., & Chakraverty, R. (2026). Enforcing mTORC1 activity in therapeutic CD4+ T cells promotes persistence but eventual immune exhaustion. Journal of Immunology. https://doi.org/10.1093/jimmun/vkag206

@article{SIL2026,
  author       = {Sillito, F. and Armbrecht, E. and O'Neill, A. T. and McIntyre, A. and Nyatondo, M. and Holler, A. and Callender, L. A. and Henson, S. M. and Stauss, H. and Chakraverty, R.},
  title        = {{Enforcing mTORC1 activity in therapeutic CD4+ T cells promotes persistence but eventual immune exhaustion}},
  journal      = {Journal of Immunology},
  year         = {2026},
  doi          = {10.1093/jimmun/vkag206},
  note         = {PMID: 42566506},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record SIL2026) [Data set]. https://mtor-atlas.org/study/SIL2026/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_SIL2026,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record SIL2026},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/SIL2026/},
  doi          = {10.5281/zenodo.22059963}
}

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