Metabolic heterogeneity underlies reciprocal fates of TH17 cell stemness and plasticity

Peer W. F. Karmaus, Xiang Chen, Seon Ah Lim, Andrés A. Herrada, Thanh-Long M. Nguyen, Beisi Xu, Yogesh Dhungana, Sherri Rankin, Wenan Chen, Celeste Rosencrance, Kai Yang, Yiping Fan, Yong Cheng, John Easton, Geoffrey Neale, Peter Vogel and Hongbo Chi ()
Additional contact information
Peer W. F. Karmaus: St Jude Children’s Research Hospital
Xiang Chen: St Jude Children’s Research Hospital
Seon Ah Lim: St Jude Children’s Research Hospital
Andrés A. Herrada: St Jude Children’s Research Hospital
Thanh-Long M. Nguyen: St Jude Children’s Research Hospital
Beisi Xu: St Jude Children’s Research Hospital
Yogesh Dhungana: St Jude Children’s Research Hospital
Sherri Rankin: St Jude Children’s Research Hospital
Wenan Chen: St Jude Children’s Research Hospital
Celeste Rosencrance: St Jude Children’s Research Hospital
Kai Yang: St Jude Children’s Research Hospital
Yiping Fan: St Jude Children’s Research Hospital
Yong Cheng: St Jude Children’s Research Hospital
John Easton: St Jude Children’s Research Hospital
Geoffrey Neale: St Jude Children’s Research Hospital
Peter Vogel: St Jude Children’s Research Hospital
Hongbo Chi: St Jude Children’s Research Hospital

Nature, 2019, vol. 565, issue 7737, 101-105

Abstract: Abstract A defining feature of adaptive immunity is the development of long-lived memory T cells to curtail infection. Recent studies have identified a unique stem-like T-cell subset amongst exhausted CD8-positive T cells in chronic infection1–3, but it remains unclear whether CD4-positive T-cell subsets with similar features exist in chronic inflammatory conditions. Amongst helper T cells, TH17 cells have prominent roles in autoimmunity and tissue inflammation and are characterized by inherent plasticity4–7, although how such plasticity is regulated is poorly understood. Here we demonstrate that TH17 cells in a mouse model of autoimmune disease are functionally and metabolically heterogeneous; they contain a subset with stemness-associated features but lower anabolic metabolism, and a reciprocal subset with higher metabolic activity that supports transdifferentiation into TH1-like cells. These two TH17-cell subsets are defined by selective expression of the transcription factors TCF-1 and T-bet, and by discrete levels of CD27 expression. We also identify signalling via the kinase complex mTORC1 as a central regulator of TH17-cell fate decisions by coordinating metabolic and transcriptional programmes. TH17 cells with disrupted mTORC1 signalling or anabolic metabolism fail to induce autoimmune neuroinflammation or to develop into TH1-like cells, but instead upregulate TCF-1 expression and acquire stemness-associated features. Single-cell RNA sequencing and experimental validation reveal heterogeneity in fate-mapped TH17 cells, and a developmental arrest in the TH1 transdifferentiation trajectory upon loss of mTORC1 activity or metabolic perturbation. Our results establish that the dichotomy of stemness and effector function underlies the heterogeneous TH17 responses and autoimmune pathogenesis, and point to previously unappreciated metabolic control of plasticity in helper T cells.

Date: 2019
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DOI: 10.1038/s41586-018-0806-7

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