Metabolic Disruption Induced by mTOR Signaling Pathway Inhibition in Regulatory T-Cell Expansion for Clinical Application

Background: Regulatory T cell (Treg) therapy is considered an alternative approach to induce tolerance in transplantation. If successful, this therapy may have implications on immunosuppression minimization/withdrawal to reduce drug-induced toxicity in patients. The aim of this study was to assess t...

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Published in:	Cells (Basel, Switzerland) Vol. 12; no. 16; p. 2066
Main Authors:	Gedaly, Roberto, Orozco, Gabriel, Ancheta, Alexandre P., Donoho, Mackenzie, Desai, Siddharth N., Chapelin, Fanny, Khurana, Aman, Lewis, Lillie J., Zhang, Cuiping, Marti, Francesc
Format:	Journal Article
Language:	English
Published:	Basel MDPI AG 01-08-2023 MDPI
Subjects:	Autophagy Bioenergetics Cell culture Cell viability Cellular signal transduction Cellular stress response Cellular therapy Drug dosages Flow cytometry Glycolysis Health aspects Immunological tolerance Immunosuppression Interleukin 2 Leukapheresis Life sciences Lymphocytes Lymphocytes T Manufacturers Manufacturing Metabolism Methods Mitochondria mTOR signaling Protein folding Rapamycin regulatory T-cells Signal transduction Software T cell receptors T cells TOR protein Toxicity Transplantation United States United States > US
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Summary:	Background: Regulatory T cell (Treg) therapy is considered an alternative approach to induce tolerance in transplantation. If successful, this therapy may have implications on immunosuppression minimization/withdrawal to reduce drug-induced toxicity in patients. The aim of this study was to assess the efficacy of the mTORC1/C2 inhibitor, AZD8055, in the manufacturing of clinically competent Treg cells and compare the effects with those induced by rapamycin (RAPA), another mTOR inhibitor commonly used in Treg expansion protocols. Methods: Primary human Treg cells were isolated from leukapheresis product. Cell viability, expansion rates, suppressive function, autophagy, mitochondrial unfolded protein response (mitoUPR), and cell metabolic profile were assessed. Results: We observed a stronger inhibition of the mTORC2 signaling pathway and downstream events triggered by Interleukin 2 (IL2)-receptor in AZD8055-treated cells compared with those treated with RAPA. AZD8055 induced progressive metabolic changes in mitochondrial respiration and glycolytic pathways that disrupted the long-term expansion and suppressive function of Tregs. Unlike RAPA, AZD8055 treatment impaired autophagy and enhanced the mitoUPR cell stress response pathway. Conclusions: A distinct pattern of mTOR inhibition by AZD, compared with RAPA, induced mitochondrial stress response and dysfunction, impaired autophagy, and disrupted cellular bioenergetics, resulting in the loss of proliferative potential and suppressive function of Treg cells.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2073-4409 2073-4409
DOI:	10.3390/cells12162066