CD27 costimulation modulates naïve T cell activation through TRAF2/SHP-1 and induces memory-associated gene regulatory networks.
Engagement of CD27 during naïve CD8+ T (TN) cell activation is critical for T cell memory generation through poorly understood mechanisms. To examine the effects of CD27 signaling during TN cell activation we designed a synthetic trimeric CD70 ligand. In conjunction with T cell receptor (TCR) stimulation, ligation of CD27 resulted in immediate receptor internalization, recruitment of TRAF2/SHP-1, and modulation of Lck and ERK/AKT signaling in cells receiving concurrent CD28 costimulation. Independent of this modulatory effect on CD28 costimulated T cells, CD27 signaling enhanced ATF2, FOXO1, and FOXP1 transcription factor circuits, which induced T cell memory rather than the effector associated gene programs observed with CD28 costimulation alone. CD27-costimulated T cells engineered with a chimeric antigen receptor (CAR) exhibited improved tumor control. CD27 signaling during TN cell activation modulates activation strength and directs memory T cell properties that may benefit therapeutic T cells engineered with CARs or T cell receptors. Overall design: We have performed Muliome-sequencing of in vitro activated human naive CD8+ T cells to assess early changes in the transcriptomic and epigenetic landscape in response to CD28 and/or CD27 costimulation. We have sequenced non-activated (naïve) T cells as well as 24h activated T cells that have been stimulated with  aCD3/aCD28 dynabeads [3:1 ratio of bead:T] or plate-bound aCD3, aCD28 and/or CD70DT (tirmeric ligand) at indicated doses [aCD3/aCD28/CD70DT; ug/mL].