Quiescence of Memory CD8⁺ T Cells Is Mediated by Regulatory T Cells through Inhibitory Receptor CTLA-4

Highlights

• Treg cells promote transition of activated effector CTLs to quiescent memory state

• Poised memory T cells require Treg cells to retain quiescence and functionality

• Soluble CTLA-4 replaces Treg cell function in promoting memory CTL quiescence

• Treg cells mediate antigen-independent memory quiescence through CTLA4-CD28-B7 axis

Summary

Immune memory cells are poised to rapidly expand and elaborate effector functions upon reinfection yet exist in a functionally quiescent state. The paradigm is that memory T cells remain inactive due to lack of T cell receptor (TCR) stimuli. Here, we report that regulatory T (Treg) cells orchestrate memory T cell quiescence by suppressing effector and proliferation programs through inhibitory receptor, cytotoxic-T-lymphocyte-associated protein-4 (CTLA-4). Loss of Treg cells resulted in activation of genome-wide transcriptional programs characteristic of effector T cells and drove transitioning as well as established memory CD8⁺ T cells toward terminally differentiated KLRG-1^hiIL-7Rα^loGzmB^hi phenotype, with compromised metabolic fitness, longevity, polyfunctionality, and protective efficacy. CTLA-4 functionally replaced Treg cells in trans to rescue memory T cell defects and restore homeostasis. These studies present the CTLA-4-CD28-CD80/CD86 axis as a potential target to accelerate vaccine-induced immunity and improve T cell memory quality in current cancer immunotherapies proposing transient Treg cell ablation.