Improving T-cell “memory” to boost immune response to vaccines

A key transcription factor in T-cell immunology is crucial to the immune system’s “memory” in recognizing threats it has faced before – and it may be possible to improve this immunological memory in vaccines, according to a new paper from scientists at the Hackensack Meridian Center for Discovery and Innovation (CDI).

The transcription factor Tcf1 essentially “pre-programs” a particular type of memory CD8+ T cells, called central memory T cells (Tcm), preparing them to respond quickly and vigorously to threats, i.e. pathogens that the immune system has already been seen, according to the article in the journal Nature Immunology, work led by CDI’s Hai-Hui “Howard” Xue.

The paper points to a way to improve the “memory” of these cells – which potentially means improving vaccines and boosting immune responses in future encounters with the same pathogens, the paper concludes.

“Vaccines train the immune system to recognize a threat without having an infection,” Xue said. “Not all vaccines are effective in obtaining sterilizing immunity. For example, the COVID-19 vaccine is protective, but there are breakthrough cases and it does not totally prevent reinfection. Science might be able to change that.

The lab investigated how Tcf1 regulates long-term immunological memory and its recall ability by using animal models to remove/eliminate Tcf1 at various points in the natural immune response.

The Xue lab therefore focused on studying the actual mechanistic actions deployed by Tcf1- and its importance for the recall response of Tcm cells. Xue and the team demonstrated through this process how Tcf1 acts as a master regulator that pulls all the strings and keeps things in order to effectively respond to a previously encountered threat.

The dynamics they observed were multifaceted down to the molecular levels, which included: Tcf1 predetermining Tcm transcriptomic changes in response to recall stimulation; Tcf1 predetermining recall-induced chromatin opening capacity in Tcm cells; Tcf1 mediating chromatin interactions in resting Tcm cells; Tcf1 preprogramming Tcm cells to mobilize glycolysis upon boost stimulation; and Tcf1 acting upstream of Id3 induction in boosted Tcm cells.

Overall, the master regulator is crucial for the body to react to threats it has already seen, whether through infection or a vaccine.

The pathway is central to Xue Lab’s research interests. For example, he and his team recently showed that Tcf1 is required by naïve cells for different reasons (i.e., to protect the identity of unstimulated CD8+ T cells).

Xue, who is one of CDI’s newest faculty arrivals, spoke at length about her work in immunology earlier this year in a profile in the “CDI Experts” series.

The latest paper shows important possible therapeutic implications for the future, he said.

“Our goal is to use Tcf1 and/or its downstream components to optimize vaccine design so that memory T cells have a more robust recall capacity and eliminate pathogens, including viruses, with greater efficiency. said Xue.

Reference: Shan Q, Hu SS, Zhu S, et al. Tcf1 preprograms the mobilization of glycolysis in central memory CD8+ T cells during recall responses. Nat Immuno. 2022:1-13. doi: 10.1038/s41590-022-01131-3.

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