Extended Data Fig. 5: Metabolically defined CD4⁺ T cell clusters have distinct metabolic activities and regulatory programs.

(a) Unsupervised clustering and UMAP of CD4⁺ T cells using expression of only genes involved in metabolic pathways, colored by metabolic cluster and by expression of key metabolic regulator genes, and (b) colored by all genes-defined cluster and by expression of phenotypic markers. (c) Left: T cell receptor (TCR) clonal expansion per cell overlaid onto UMAP plot. Right: frequency of TCR clonal expansions per metabolic cluster. (d) Heatmap of mean expression of key metabolic regulator genes, phenotypic genes and proteins, and top 10 most active metabolic fluxes for each metabolic cluster in pseudobulk. (e) Metabolic pathway activities of CD4⁺ T cell metabolic clusters in pseudobulk among all patients combined, with and without the proliferative and cytotoxic cell clusters (metabolic clusters 6 and 4, respectively). (f) Metabolic pathway activities that are significantly correlated with WHO score by two-sided Spearman’s rank correlation (p < 0.05; labeled on right) for all CD4⁺ T cells per patient, for only T_reg cells, only cytotoxic cells (metabolic cluster 4), and only proliferative cells (metabolic cluster 6). Exact p-values are in Supplementary Table 7. (g) Kernel density estimates of expressions of genes included in key energy-producing metabolic pathways for CD4⁺ T cells among patients with mild disease/healthy subjects (WHO 0–2) and patients with severe disease (WHO 5–7) in pseudobulk and separately for metabolic clusters 4 and 6 and T_reg cells.