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Inhibition of mTORC2/Akt signaling to enhance the therapeutic potential of CD8 T cells

CD8 T cells mediate protective immune responses against infections and cancer. Upon infection, antigen-specific naïve CD8 T cells are activated and differentiate into short-lived effector (SLEC) and memory precursor cells (MPEC). The T cell intrinsic signaling pathways underlying this differentiation remain largely unresolved. Here we show that Rictor, the core component of mammalian target of rapamycin complex 2 (mTORC2), regulates SLEC and MPEC commitment. Rictor deficient T cells form enhanced memory without dampening effector function, have increased IL-2 secretion capacity and mediate more potent recall responses. Mechanistically, enhanced memory formation in the absence of functional mTORC2 was associated with transcriptional and metabolic reprogramming by Eomes and Tcf-1 upregulation, repression of T-bet and nuclear stabilization of Foxo1. Elimination of Foxo1 reversed the increased MPECs differentiation and IL-2 production in Rictor KO mice. Effective T cell therapy against cancer depends highly on the generation of long-term persistent memory CD8 T cells. Our preliminary data show that Rictor deficient CD8 T cells show superior tumor protection effects in mouse melanoma model. Together, our study identifies mTORC2 as a central regulator of CD8 T cell differentiation and inhibition of mTORC2 or Akt might represent an effective strategy for both adoptive cell transfer and vaccine-based cancer therapies.

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Correspondence to Lianjun Zhang.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Keywords

  • Protective Immune Response
  • Mouse Melanoma
  • Intrinsic Signaling
  • Metabolic Reprogram
  • Adoptive Cell Transfer