Extended Data Fig. 7: Although priming by hepatocytes initiates a unique dysfunctional program, hepatocellular antigen persistence may gradually trigger an additional exhaustion signature.

a–d, Left, number of top 100 genes from Cor93 T cells recovered from the livers of wild-type mice transduced with rLCMV-core (a, c) or of MUP-core (b, d) mice reaching log₂(RPKM) >1 in the indicated conditions in RNA-seq data from splenic LCMV-specific effector or exhausted CD8⁺ T cells³⁰ (a, b) or splenic LCMV-specific exhausted CD8⁺ T cells³¹ (c, d). Right, box plots showing the expression levels of top 100 genes from Cor93 T cells recovered from livers of WT + rLCMV-core mice (a, c) or MUP-core mice (b, d) in the indicated conditions in RNA-seq data from splenic LCMV-specific effector or exhausted CD8⁺ T cells³⁰ (a, b) or splenic LCMV-specific exhausted CD8⁺ T cells³¹ (c, d). Naive (n = 2), effector (n = 2), exhausted (n = 2). e, f, Left, number of top 100 genes in Cor93 T cells isolated from livers of wild-type + rLCMV-core mice (e) or from MUP-core mice (f) expressed (log₂(normalized data) > 65th percentile of the full distribution) in the indicated conditions in microarray data from tolerant self-antigen-specific CD8⁺ T cells³². Right, box plots showing the expression levels of genes retrieved in the dataset among the top 100 genes in Cor93 T cells isolated from the livers of wild-type + rLCMV-core (e) or MUP-core (f) mice in the indicated conditions in microarray data from tolerant self-antigen-specific CD8⁺ T cells³². Only genes for which microarray probes were retrieved were kept for these analyses. Naive (n = 3), tolerant (n = 3). *P < 0.05, **P < 0.01, ***P < 0.001, two-tailed Wilcoxon rank-sum test. All box plots are represented as in Fig. 3f, and dots represent the expression distribution of the set of 100 genes. g–i, Enrichment plot showing the results of a GSEAPreanked analysis (Kolmogorow–Smirnov statistics) performed on genes expressed in CD8⁺ T cells from wild-type + rLCMV-core or MUP-core mice (gene lists ranked by log(FC_RPKM)) and using as gene set a curated list of genes induced in exhausted CD8⁺ T cells (n = 2) but not in effector CD8⁺ T cells (n = 2) as compared to naive cells (n = 2)³⁰. NES and P values are reported for each time point.