2. Academic Validation
  3. Signaling via a CD27-TRAF2-SHP-1 axis during naive T cell activation promotes memory-associated gene regulatory networks

Signaling via a CD27-TRAF2-SHP-1 axis during naive T cell activation promotes memory-associated gene regulatory networks

  • Immunity. 2024 Feb 13;57(2):287-302.e12. doi: 10.1016/j.immuni.2024.01.011.
Carla A Jaeger-Ruckstuhl 1,  Yun Lo 2,  Elena Fulton 2,  Olivia G Waltner 2,  Tamer B Shabaneh 2,  Sylvain Simon 2,  Pranav V Muthuraman 2,  Colin E Correnti 2,  Oliver J Newsom 3,  Ian A Engstrom 3,  Sami B Kanaan 2,  Shruti S Bhise 2,  Jobelle M C Peralta 2,  Raymond Ruff 4,  Jason P Price 4,  Sylvia M Stull 2,  Andrew R Stevens 2,  Grace Bugos 2,  Mitchell G Kluesner 3,  Valentin Voillet 5,  Vishaka Muhunthan 2,  Fionnuala Morrish 2,  James M Olson 4,  Raphaël Gottardo 6,  Jay F Sarthy 7,  Steven Henikoff 8,  Lucas B Sullivan 3,  Scott N Furlan 4,  Stanley R Riddell 9
Affiliations

Affiliations

  • 1 Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Electronic address: cjaeger@fredhutch.org.
  • 2 Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  • 3 Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  • 4 Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Seattle Children's Hospital, Seattle, WA 98105, USA.
  • 5 Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  • 6 Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Department of Statistics, University of Washington, Seattle, WA 98195, USA; Swiss Institute of Bioinformatics, University of Lausanne and Lausanne University Hospital, Lausanne 1011, Switzerland.
  • 7 Seattle Children's Hospital, Seattle, WA 98105, USA; Basic Science Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  • 8 Basic Science Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA.
  • 9 Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA. Electronic address: sriddell@fredhutch.org.
PMID: 38354704 DOI: 10.1016/j.immuni.2024.01.011
Abstract

The interaction of the tumor necrosis factor receptor (TNFR) family member CD27 on naive CD8+ T (Tn) cells with homotrimeric CD70 on antigen-presenting cells (APCs) is necessary for T cell memory fate determination. Here, we examined CD27 signaling during Tn cell activation and differentiation. In conjunction with T cell receptor (TCR) stimulation, ligation of CD27 by a synthetic trimeric CD70 ligand triggered CD27 internalization and degradation, suggesting active regulation of this signaling axis. Internalized CD27 recruited the signaling adaptor TRAF2 and the Phosphatase SHP-1, thereby modulating TCR and CD28 signals. CD27-mediated modulation of TCR signals promoted transcription factor circuits that induced memory rather than effector associated gene programs, which are induced by CD28 costimulation. CD27-costimulated chimeric antigen receptor (CAR)-engineered T cells exhibited improved tumor control compared with CD28-costimulated CAR-T cells. Thus, CD27 signaling during Tn cell activation promotes memory properties with relevance to T cell immunotherapy.

Keywords

CAR-T cell therapy; CD27; CD8(+) T cell; SHP-1 phosphatase; chimeric antigen receptor; costimulation; memory and effector fate determination; naive T cell activation.

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