Functional memory T cells are derived from exhausted clones and expanded by checkpoint blockade

Area of Science:

• Immunology
• T cell biology
• Cancer immunotherapy

Background:

• Immune checkpoint blockade (ICB) aids tumor clearance by T cells, improving patient survival.
• The ability of exhausted CD8+ T cells (Tex) to form memory after chronic antigen exposure and clearance is not well understood.

Purpose of the Study:

• To investigate the memory formation capacity of exhausted CD8+ T cells following chronic antigen exposure.
• To determine the characteristics and lineage of memory T cells derived from Tex.
• To assess the impact of immune checkpoint blockade on Tex-derived memory formation.

Main Methods:

• Longitudinal single-cell RNA sequencing, T cell receptor sequencing, and ATAC-sequencing were performed on antigen-specific T cells.
• Lineage tracing was used to track the origin and recall response of Tex-derived memory clones.
• Mice with chronic lymphocytic choriomeningitis virus (LCMV) infection were treated with αPD-L1.

Main Results:

• A robust population of memory CD8+ T cells, resembling central memory T cells (Tcm), formed after chronic LCMV infection clearance.
• Tex-derived memory clones were identified as a distinct lineage, persisting long-term and expanding upon rechallenge.
• αPD-L1 therapy preferentially expanded clones that generated Tcm after chronic infection.

Conclusions:

• Chronically stimulated T cells can differentiate into bona fide functional memory T cells, similar to those from acute infections.
• This pathway has significant implications for enhancing immune memory in cancer via checkpoint blockade and vaccination.
• Tex are a viable source of long-lasting immune memory crucial for adaptive immunity.