Metabolic heterogeneity underlies reciprocal fates of T17 cell stemness and plasticity.

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 infection, but it remains unclear whether CD4-positive T-cell subsets with similar features exist in chronic inflammatory conditions. Amongst helper T cells, T17 cells have prominent roles in autoimmunity and tissue inflammation and are characterized by inherent plasticity, although how such plasticity is regulated is poorly understood. Here we demonstrate that T17 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 T1-like cells. These two T17-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 T17-cell fate decisions by coordinating metabolic and transcriptional programmes. T17 cells with disrupted mTORC1 signalling or anabolic metabolism fail to induce autoimmune neuroinflammation or to develop into T1-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 T17 cells, and a developmental arrest in the T1 transdifferentiation trajectory upon loss of mTORC1 activity or metabolic perturbation. Our results establish that the dichotomy of stemness and effector function underlies the heterogeneous T17 responses and autoimmune pathogenesis, and point to previously unappreciated metabolic control of plasticity in helper T cells.