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.

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.

MeSH terms

  • CD27 Ligand / genetics
  • CD27 Ligand / metabolism
  • CD28 Antigens* / metabolism
  • CD8-Positive T-Lymphocytes
  • Gene Regulatory Networks*
  • Lymphocyte Activation
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction
  • TNF Receptor-Associated Factor 2 / genetics
  • TNF Receptor-Associated Factor 2 / metabolism
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / genetics
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / metabolism

Substances

  • TNF Receptor-Associated Factor 2
  • CD28 Antigens
  • Receptors, Antigen, T-Cell
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • CD27 Ligand