Functional memory T cells are derived from exhausted clones and expanded by checkpoint blockade [scRNA/TCR-seq]

Seurat Objects froms scRNA/TCR-seq Data Associated with the manuscript: Functional memory T cells are derived from exhausted clones and expanded by checkpoint blockade

This dataset is a supplement to our Github Repostory which contains raw data and R markdown files neccesary to generate all figures from our manuscript. 

Three (3) Seurat Objects are available on this page 

1. scRNA/TCR-seq atlas: Analysis of scRNA/TCR-seq of GP33+ cells (+/- CD62L enrichment): Fig. 1,2 and Extended Data Fig. 1,3,4
2. Polyclonal Rechallenge: scRNA/TCR-seq from clonal tracing of CD8+ T cells from 100+ dpi of acuure and chronic infection during rechallenge:  Fig. 4 and Extended Data Fig. 6,7
3. scRNA/TCR-seq aPDL1: Analysis of scRNA/TCR-seq of GP33+ cells after aPDL1 Treatment: Fig. 5 and Extended Data Fig. 8

Raw single cell data are on NCBI GEO at accession numbers GSE285411 (scRNA/TCR-seq atlas), GSE285414 (scRNA/TCR-seq post-rechallenge), and GSE285412 (scRNA/TCR-seq αPD-L1).

Manuscript Abstract:

Immune checkpoint blockade can facilitate tumor clearance by T cells, resulting in long term patient survival. However, the capacity of exhausted CD8+ T cells (Tex), present during chronic antigen exposure, to form memory after antigen clearance remains unclear. Here, we performed longitudinal single cell RNA/T cell receptor sequencing and ATAC-sequencing on antigen-specific T cells after the peripheral clearance of chronic lymphocytic choriomeningitis virus infection. These data revealed the formation of a robust population of memory CD8+ T cells that transcriptionally, epigenetically, and functionally resemble central memory T cells (Tcm) that form after clearance of acute infection. To lineage trace the origin and memory recall response of Tex-derived memory clones, we utilized T cell receptor sequencing over the course of primary infection and rechallenge. We show that chronic Tcm are a clonally distinct lineage of Tex derived from progenitor exhausted cells, persist long-term in the absence of antigen, and undergo rapid clonal expansion during rechallenge. Finally, we demonstrate that αPD-L1 immune checkpoint blockade selectively expands clones which form Tcm after clearance. Together, these data support the concept that chronically stimulated T cells form bona fide functional memory T cells through an analogous differentiation pathway to acutely stimulated T cells, which may have significant implications for enhancing immune memory to cancer through checkpoint blockade and vaccination.