Chronic antiviral CD8+ T cell responses are maintained by precursors of exhausted T (TPEX) cells, which possess high self-renewal and developmental capacity that are critical for mediating the response to therapeutic checkpoint blockade (ICB). However, the spatial context and signals that regulate their differentiation remain poorly defined. We show that during chronic infection, lymph nodes harbor T cells that possess superior proliferative fitness, polyfunctionality and exclusively drive systemic response to ICB. Lymph nodes uniquely support the differentiation of stem-like CD62L+ TPEX to effector-like CX3CR1+ progeny, which constitute a distinct exhausted T cell lineage dependent on the transcription factor KLF2. Lastly, lymph node-specific migratory dendritic cells are key orchestrators of this differentiation program by providing high amounts of antigen and costimulatory signals to T cells.
Cell cell interaction analysis and trajectory analysis for Tsui et al.:
- cell type classification with SingleR
- Slingshot trajectory analysis
- Infer cell-cell interaction with Cellchat
- annotate ligand receptor pairs with broad immunological terms
- Correct for confounders using muVI using GO terms identified with GOEA for problematic cell clusters
- Determined Pseudotime and branches with Palantir
- Calculated cell transition probabilities and infered driver genes with CellRank