TCF-1 regulates HIV-specific CD8+ T cell expansion capacity
Rachel L. Rutishauser, … , Joseph M. McCune, Peter W. Hunt
Rachel L. Rutishauser, … , Joseph M. McCune, Peter W. Hunt
Published December 22, 2020
Citation Information: JCI Insight. 2021;6(3):e136648. https://doi.org/10.1172/jci.insight.136648.
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Research Article AIDS/HIV Immunology

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

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.

Authors

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

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Figure 1

TCF-1 expression is elevated in HIV- and SIV-specific CD8+ T cells from controllers.

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TCF-1 expression is elevated in HIV- and SIV-specific CD8+ T cells from ...
(A) Frequency of peripheral blood multimer+ HIV–specific CD8+ T cells. (B) Proliferation of HIV-specific CD8+ T cells in response to 6-day in vitro cognate peptide stimulation as measured by dilution of cell-trace violet (CTV). (C) Gating strategy (left: green, multimer+ from controller; gray, bulk CD8+ T cells) and distribution (right) of effector-memory phenotypes amongst multimer+ cells (TN, naive [gate includes, and likely primarily contains, CD95+ stem-cell memory cells, TSCM]; TCM, central memory; TTM, transitional memory; TEM, effector memory; TEMRA, effector memory-RA, separated by level of CD27 expression). (D) Gating (top left; TCF-1+ population gated based on CD8+ TN population from an HIV-uninfected participant, blue), representative flow plots (top right; median [range]), and summary data (bottom) showing TCF-1 expression in multimer+ HIV–specific CD8+ T cells from viremic (VIR; magenta), ART-suppressed (ARTs; black), and controller (C; green) individuals of all multimer specificities (left) and within the HIV Gag/HLA-A*02:SL9 multimer+ population (right). (E) TCF-1 expression in the SIV Gag/Mamu-A*01:CM9 multimer+ population from viremic and controller macaques. Phenotypes assessed by flow cytometry. FMO, fluorescence-minus-1 control. Box plots: median ± IQR. The human studies included data from a maximum of n = 13 viremic, 10 ART-suppressed, and 12 controller participants (as indicated in each figure), some with 2 multimer specificities. The macaque studies included n = 6 viremic and 4 controller animals. Linear mixed effects models to account for clustering within participants (A, C, D), Kruskal-Wallis followed by Dunn’s multiple comparison testing (B), Wilcoxon’s rank sum (E) were used.