1. TCF-1 regulates HIV-specific CD8+ T cell expansion capacity.
- Author
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Rutishauser RL, Deguit CDT, Hiatt J, Blaeschke F, Roth TL, Wang L, Raymond KA, Starke CE, Mudd JC, Chen W, Smullin C, Matus-Nicodemos R, Hoh R, Krone M, Hecht FM, Pilcher CD, Martin JN, Koup RA, Douek DC, Brenchley JM, Sékaly RP, Pillai SK, Marson A, Deeks SG, McCune JM, and Hunt PW
- Subjects
- Adult, Aged, Animals, Female, Gene Knockout Techniques, HIV Antigens genetics, HIV Antigens immunology, HIV-1 genetics, Humans, Immunologic Memory, Macaca mulatta, Male, Middle Aged, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus immunology, T Cell Transcription Factor 1 antagonists & inhibitors, T Cell Transcription Factor 1 genetics, Viral Load immunology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes virology, HIV Infections immunology, HIV Infections virology, HIV-1 immunology, T Cell Transcription Factor 1 immunology
- Abstract
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.
- Published
- 2021
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