Scientists at UW Medicine, University of Washington, and their collaborators have pinpointed exactly when cytotoxic T lymphocytes form memories during infection. They also examined the epigenetic switch that underlies flexible memory formation in these cells. Their findings were published in Immunity in a paper titled, “Reversible, tunable epigenetic silencing of TCF1 generates flexibility in the T cell memory decision.”

Insights from studies like this could lead to the development of novel methods of boosting long-term immune protection against various infectious diseases and cancers. 

To understand when T cells decide to form memories about pathogens, the researchers used transcriptomic data and real-time, live imaging to observe the cells over the trajectory of their entire lineage. Their experiments “revealed an unexpected degree of flexibility in memory decision making, whereby memory T cells are generated at multiple phases during the immune response,” the researchers wrote. “After encountering a pathogen, T cells decide early whether to form a memory, or alternatively, to become an effector cell, which has potent cell-killing abilities but is short-lived.”

They also uncovered details about a molecular switch involved in how T-cell memories are formed. Findings reported in the paper show that this epigenetic switch reversibly silences Tcf7, a key memory regulatory gene, “in response to stimulatory signals due to infection.” Importantly, “this switch is reversible when these signals are gone, thus enabling cells that have gone down the effector trajectory to reverse their course,” the researchers wrote.

Flexibility in making memory decisions is important because it allows T cells to mount the most effective immune response depending on the pathogenic threat. Using a mathematical model, the scientists demonstrated that T cells could form memories of virulent pathogens that require a large-scale immune response as well as memories of slow-dividing pathogens that try to evade the immune system. This ability to “make memory fate decisions at multiple junctures during an infection might also allow for greater responsiveness during the evolving situation of an immune challenge,” the team noted. 

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