Figure 5.

Heterogeneity among CD8⁺ NK-like terminally differentiated effector memory T cells re-expressing CD45RA. (A) Integrated UMAP projection of subclustered CD8⁺ NK-like T_EMRA cells (CD16⁺ CD8⁺ T_EMRA cells) (n = 1,320). (B) Average proportion of CD16⁺ CD8⁺ T_EMRA subsets for the three conditions. Cell type proportions per patient are reported in Figure S6A . (C) Average expression of marker genes differentially expressed in the six CD16⁺ CD8⁺ T_EMRA subsets. (D) Surface expression (CITE-seq) of IL7R and HLA-DR per CD16⁺ CD8⁺ T_EMRA subtype. (E) NK cell signature scores of the six CD16⁺ CD8⁺ T_EMRA subsets. (F) Differentially expressed genes in CD16⁺ CD8⁺ T_EMRA-2 cells between the severe and the mild disease condition. (G) Selected significantly enriched gene sets for genes differentially expressed in the indicated CD16⁺ CD8⁺ T_EMRA subtypes between mild and severe disease groups. Positive normalized enrichment scores (NES) indicate enrichment in the severe disease condition. (H) PI3K pathway activity in CD16⁺ CD8⁺ T_EMRA-3 cells estimated with PROGENy. Significance was tested using Wilcoxon rank sum test. All PROGENy pathways are reported in Figure S6G . (I) Differential transcription factor activity (DoRothEA) estimated with msviper in CD16⁺ CD8⁺ T_EMRA-1 cells between the severe and the mild condition. Positive NES values indicate increased activity in severe SARS-CoV-2 infection. (J) Different functional scores applied to CD16⁺ CD8⁺ T_EMRA-1 cells and compared between severe and mild COVID-19 (Wilcoxon rank sum test). DGE, differential gene expression; log2FC, log2 fold change; GSEA, gene set enrichment analysis; NES, normalized enrichment score; PI3K, Phosphoinositide 3-kinase; TF, transcription factor.