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

JCI Insight. 2021 Feb 8;6(3):e136648. doi: 10.1172/jci.insight.136648.


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.

Keywords: AIDS/HIV; Adaptive immunity; Immunology; T cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / virology*
  • Female
  • Gene Knockout Techniques
  • HIV Antigens / genetics
  • HIV Antigens / immunology
  • HIV Infections / immunology*
  • HIV Infections / virology*
  • HIV-1 / genetics
  • HIV-1 / immunology*
  • 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
  • T Cell Transcription Factor 1 / immunology*
  • Viral Load / immunology


  • HIV Antigens
  • T Cell Transcription Factor 1
  • TCF7 protein, human