TCF-1 regulates HIV-specific CD8+ T cell expansion capacity.

Although many HIV cure strategies seek to expand HIV-specific CD8+ T cells to control the virus, all are likely to fail if cellular exhaustion is not prevented. A loss in stem-like memory properties (i.e., the ability to proliferate and generate secondary effector cells) is a key feature of exhaustion; little is known, however, about how these properties are regulated in human virus-specific CD8+ T cells. We found that virus-specific CD8+ T cells from humans and nonhuman primates naturally controlling HIV/SIV infection express more of the transcription factor TCF-1 than noncontrollers. HIV-specific CD8+ T cell TCF-1 expression correlated with memory marker expression and expansion capacity and declined with antigenic stimulation. CRISPR-Cas9 editing of TCF-1 in human primary T cells demonstrated a direct role in regulating expansion capacity. Collectively, these data suggest that TCF-1 contributes to the regulation of the stem-like memory property of secondary expansion capacity of HIV-specific CD8+ T cells, and they provide a rationale for exploring the enhancement of this pathway in T cell-based therapeutic strategies for HIV.

Citation

Rachel L Rutishauser, Christian Deo T Deguit, Joseph Hiatt, Franziska Blaeschke, Theodore L Roth, Lynn Wang, Kyle A Raymond, Carly E Starke, Joseph C Mudd, Wenxuan Chen, Carolyn Smullin, Rodrigo Matus-Nicodemos, Rebecca Hoh, Melissa Krone, Frederick M Hecht, Christopher D Pilcher, Jeffrey N Martin, Richard A Koup, Daniel C Douek, Jason M Brenchley, Rafick-Pierre Sékaly, Satish K Pillai, Alexander Marson, Steven G Deeks, Joseph M McCune, Peter W Hunt. TCF-1 regulates HIV-specific CD8+ T cell expansion capacity. JCI insight. 2021 Feb 08;6(3)

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PMID: 33351785

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