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

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

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