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
  • 1. Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Electronic address: [email protected].
  • 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: [email protected].
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.