Hot from the hell of pathogen attack, battle-hardened T cells, or killer T cells, need to cool down and reintegrate with civilized immune society. With the help of regulatory T cells, killer T cells enter a quiescent state, but remain alert to future calls to duty. How do regulatory T cells manage to restrain killer T cells, keeping them in reserve while preventing autoimmunity? The secret, it turns out, it a cell surface protein, cytotoxic T-lymphocyte associated protein-4 (CTLA-4).

According to researchers at the University of Pennsylvania, soluble CTLA-4 can substitute for regulatory T cells in keeping killer T cells on a short leash. This finding, reported June 16 in the journal Immunity, could have a far reaching impact on immunity to a wide array of infectious diseases and even cancer vaccines and tumor immunity.

For example, by taking hold of the immune system’s leash—the CTLA-4-CD28-CD80/CD86 axis—clinicians could control the immune system as needed. According to the University of Pennsylvania researchers, accelerating T cell memory following an immunization could lead to vaccines that become effective more quickly. Healthcare workers who are preparing to go to the field to fight an epidemic might only need to wait days, rather than weeks, for their vaccinations to become effective.

The findings could also help guide the development of future vaccines.

The Immunity article—“Quiescence of Memory CD8+ T Cells Is Mediated by Regulatory T Cells through Inhibitory Receptor CTLA-4”—reported that regulatory T cells orchestrate memory T cell quiescence by suppressing effector and proliferation programs through the inhibitory receptor CTLA-4.

“Loss of [regulatory T] 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 [a] terminally differentiated … phenotype, with compromised metabolic fitness, longevity, polyfunctionality, and protective efficacy,” the study's authors wrote. “CTLA-4 functionally replaced [regulatory T] cells in trans to rescue memory T cell defects and restore homeostasis.”

The University of Pennsylvania team, led by Surojit Sarkar, Ph.D., and Vandana Kalia, Ph.D., both assistant professors of immunology, concluded that the CTLA-4-CD28-CD80/CD86 axis could be an attractive target to accelerate vaccine-induced immunity. Manipulating the axis could also improve T cell memory quality in cancer immunotherapies that are meant to provide transient regulatory T cell ablation.

“Once the T cells clear the pathogen, just like in warfare, you do not leave your weapons drawn, you holster them,” said Dr. Sarkar. “In the case of the immune system, those charged killer T cells also downregulate their killer machinery.”

“I like to think of regulatory T cells as the police of our immune system—their job is to keep other immune cells in check, said Dr. Kalia. “In the case of memory T cells, regulatory T cells serve to keep their killer functions in check and help maintain them in a quiescent, yet ready to kill, state.”

“What our study is doing is looking at the basic concepts of how the immune system's memory develops and such fundamental information is critical for advancing our current vaccine development efforts,” Dr. Kalia added.

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