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

Rachel L Rutishauser,Richard A Koup,Alexander Marson,Carolyn Smullin,Wenxuan Chen,Theodore L Roth,Satish K Pillai,Kyle A Raymond,Lynn Wang,Jason M Brenchley,Carly E Starke,Steven G Deeks,Jeffrey N Martin,Rebecca Hoh,Daniel C Douek,Joseph M Mccune,Joseph C Mudd,Joseph Hiatt,Franziska Blaeschke,Peter W Hunt,Melissa Krone,Christian Deo T Deguit,Christopher D Pilcher,Frederick Hecht ,Rafick‐Pierre Sékaly ,Rodrigo Matus‐Nicodemos

doi:10.1172/jci.insight.136648

Rachel L Rutishauser, Richard A Koup + Show 24 more

Open Access

https://doi.org/10.1172/jci.insight.136648

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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.

Highlights

In the vast majority of individuals, infection with human immunodeficiency virus-1 (HIV) leads to chronic viremia that is not controlled by natural host immune responses
We identified HLA-typed participants with HIV enrolled in the San Francisco– based SCOPE cohort who had detectable HIV-specific CD8+ T cell responses in the peripheral blood by MHC Class I multimer staining (“multimer+”)
The goal of many immune-based strategies that aim to enhance the control of HIV is to elicit functional, nonexhausted, and durable HIV-specific CD8+ T cells that have the stem-like memory T cell capacity to rapidly expand into secondary effector cells that can kill HIV-infected cells [10, 12]

Summary

Introduction

In the vast majority of individuals, infection with human immunodeficiency virus-1 (HIV) leads to chronic viremia that is not controlled by natural host immune responses. Antigen-specific CD8+ T cell exhaustion occurs in the setting of chronic antigen exposure, and exhausted CD8+ T cells are defined by their impaired proliferation, effector cytokine production, and killing capacity after T cell receptor (TCR) stimulation with peptide [4]. Even though they can initially control the viral load (VL) [5,6,7,8,9], HIV-specific CD8+ T cells that persist during the chronic phase of infection fail to eradicate infected cells from the body. While several cell-intrinsic factors — including the expression of PD-1 [1, 2] and other coinhibitory receptors [25,26,27], activation of caspase-8 [28], and the expression of the transcription factor BATF [29] — are known to regulate HIV-specific CD8+ T cell dysfunction, little is known about the molecular pathways that support the stem-like memory properties observed in HIV-specific CD8+ T cells from controllers

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