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CDI Laboratory Identifies Critical Regulators Controlling T-Cell Homeostasis

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What You Need to Know

The laboratory of Hai-Hui “Howard” Xue at the Hackensack Meridian Center for Discovery and Innovation (CDI) published its findings about the complex and cascading molecular interactions modulating T-cell immunology in the August issue of the journal Nature Immunology. Their findings could hold the key to better modulating the human immune system to fight cancer and produce vaccines of the future.

This is the second Nature Immunology paper from the CDI this year. This paper seeks to understand how T cell homeostasis is regulated beyond the known classical pathways. The findings indicate that T cells can be induced to cycling while maintaining their naive status which could change the way we harness the power of T cells heading forward.

The Xue lab in the two successive Nature Immunology publications has focused on a key dynamic of T-cell immunology: the Tcf1 transcription factor and its far-reaching molecular complexity. 

Watch Xue’s Lab’s findings in action with this animation.

About the March 2022 Publication

Tcf1 is crucial to the immune system’s “memory” in recognizing threats it has already faced before.

The Tcf1 transcription factor essentially “preprograms” a particular type of memory CD8+ T cells, called T central memory (Tcm) cells, prepping them to respond quickly and robustly to known threats, i.e., pathogens that the immune system has seen before, according to the paper earlier this year in the same journal.

That first paper pointed toward a way to improve the “memory” of these cells – meaning potentially improving vaccines and boosting immune responses in future encounters with the same pathogens.

About the August 2022 Publication

The new paper brings the results a step further in complexity. The scientists found that Tcf1 and Lef1 (an homologue of Tcf1) are critical in recruiting the CCCTC-binding factor (known as CTCF), a well-characterized architectural protein and a versatile transcription regulator, to key parts of the genome of the CD8+ T-cells. By so doing, Tcf1 fosters key chromatin interactions – and associated crucial gene expression programs of the CD8+ T-cells.

Xue and colleagues proved how central the Tcf1 was by “knocking out” the transcription factors in animal models. In so doing, it compromised the ability of CD8+ T cells to respond to two key interleukin cytokines that drive cell cycle progression to maintain a steady pool size and sustain immune competence. 

By perfoming genome-wide analyses in the T cells, the scientists found significant overlap in both the Tcf1 and the CTCF binding on the CD8+ genome, thereby further demonstrating their cooperativity in multiple cellular processes. 

Ultimately, they found that Tcf1 and Lef1, in working with the CTCF, provide “constant supervision” of this genomic architecture and  confer flexibility. Together, they translate cytokine-derived signals into protein synthesis and DNA replication that underlie homeostatic proliferation of CD8+ T cells. 

“The prevalent overlap between Tcf1 and CTCF is unusual, and most importantly, the access of CTCF to the CD8 T-cell genome depends on Tcf1 at critical locations,” said Xue. “Also important to the biology side of things: both factors controlled the same set of genes regulating homeostatic proliferation. 

“This signifies Tcf1 and CTCF as important targets to modulate so as to  amplify T cells in their naïve state, which will  have real implications in where science goes to harness the power of T cells in cellular therapy,” Xue added.