Metabolic heterogeneity underlies reciprocal fates of T(H)17 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 in exhausted CD8(+) T cells in chronic infection(1–3), but it remains unclear whether CD4(+) T cell subsets with similar features exist in chronic inflammatory conditions. Among helper T cells, T(H)17 cells play prominent roles in autoimmunity and tissue inflammation and are characterized by inherent plasticity(4–7), although the regulation of plasticity is poorly understood. Here we demonstrate that T(H)17 cells in autoimmune disease are functionally and metabolically heterogeneous and contain a subset with stemness-associated features but lower anabolic metabolism, and a reciprocal subset with higher metabolic activity that supports the transdifferentiation into T(H)1 cells. These two T(H)17 cell subsets are defined by selective expression of transcription factors TCF-1 and T-bet, and discrete CD27 expression levels. Moreover, we identify mTORC1 signaling as a central regulator to orchestrate T(H)17 cell fates by coordinating metabolic and transcriptional programs. T(H)17 cells with disrupted mTORC1 or anabolic metabolism fail to induce autoimmune neuroinflammation or develop into T(H)1-like cells, but instead upregulate TCF-1 expression and activity and acquire stemness-associated features. Single cell RNA-sequencing and experimental validation reveal heterogeneity in fate-mapped T(H)17 cells, and a developmental arrest in the T(H)1 transdifferentiation trajectory upon mTORC1 deletion or metabolic perturbation. Our results establish that the dichotomy of stemness and effector function underlies the heterogeneous T(H)17 responses and autoimmune pathogenesis, and point to previously unappreciated metabolic control of helper T cell plasticity.