Signaling via a CD27-TRAF2-SHP-1 axis during naive T cell activation promotes memory-associated gene regulatory networks
Carla A. Jaeger-Ruckstuhl, Yun Lo, Elena Fulton, Olivia G. Waltner, Tamer B. Shabaneh, Sylvain Simon, Pranav V. Muthuraman, Colin Correnti, Oliver J. Newsom, I. Engström, Sami B. Kanaan, Shruti S. Bhise, Jobelle M.C. Peralta, Raymond Ruff, Jason P. Price, Sylvia M. Stull, Andrew R. Stevens, Grace Bugos, Mitchell G. Kluesner, Valentin Voillet, Vishaka Muhunthan, Fionnuala Morrish, James M. Olson, Raphaël Gottardo, Jay F. Sarthy, Steven Henikoff, Lucas B. Sullivan, Scott N. Furlan, Stanley R. Riddell
Abstract
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.