PD-1+TCF-1+ stem-like CD8+ T cells result from helpless priming and rely on CD4+ T-cell help to complete their cytotoxic effector differentiation

ABSTRACT: In cancer and chronic infection, antigen-specific CD8+ T cells can be in a stem-like/progenitor exhausted PD-1+TCF-1+ state that progresses into terminal exhaustion. These stem-like cells are important, since they are the responders to PD-1 targeted immunotherapy. Here, we have addressed the role of CD4+ T-cell help during priming in the generation and differentiation fate of stem-like CD8+ T cells. We demonstrate in a vaccination model that during priming, antigen-specific CD8+ T cells initially have a stem-like phenotype, but proliferate and differentiate within the draining lymph node (dLN) into cytotoxic effector cells when help signals are present. In absence of help, stem-like CD8+ T cells accumulate in the dLN and inefficiently go into the circulation. Stem-like cells can still develop into effector cells when help signals are provided after priming. An immunogenic tumor such as MC-38 does not prime helped effector cells but only stem-like cells that become exhausted in the tumor micro-environment (TME). Stem-like CD8+ T cells raised in absence of CD4+ T-cell help in our vaccination model share their transcriptome with stem-like cells defined in mouse models of chronic infection and cancer. Our data support that stem-like CD8+ T cells lie at the bifurcation point of CD8+ T-cell effector- and exhaustion trajectories. Thus, we define stem-like CD8+ T cells in vaccination, chronic infection and cancer as the same helpless cells and CD4+ T-cell help as key signal that allows their expansion and CTL effector differentiation. These findings promote CD4+ T-cell help as key ingredient in all cancer immunotherapy strategies.

ORGANISM(S): Mus musculus

PROVIDER: GSE249046 | GEO | 2025/12/01

REPOSITORIES: GEO