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CD27 costimulation modulates naïve T cell activation through TRAF2/SHP-1 and induces memory-associated gene regulatory networks.

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244834 | GEO | 2023/10/10

REPOSITORIES: GEO

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Project description:Some unicellular organisms exhibit collective decision-making through intercellular communication once a quorum of members sense an environmental stress. Whether T cells at different states of differentiation may also synchronize their behavior on a population basis through direct interactions remains unclear. We report that memory CD8+ T cells (TMem) directly interact with naive T cells (TN) during priming, affecting the phenotypic, functional, transcriptional and metabolic differentiation of TN-derived progeny. This previously unrecognized, contact and concentration-dependent interaction between naive (TN) and memory CD8+ T cells (TMem) directly enhanced TN effector differentiation through non-apoptotic Fas signaling resulting in downstream Akt pathway activation. TN primed with TMem exhibited significantly impaired persistence and antitumor activity compared with TN primed alone. Disruption of FasL-Fas signaling in TN cells limited differentiation and enhanced anti-tumor immunity while provision of exogenous FasL in the absence of TMem impaired anti-tumor immunity by augmenting TN differentiation. These findings reveal that the full therapeutic potential of TN-derived cells for adoptive immunotherapy requires physical separation from TMem prior to priming or antagonism of Fas-signaling. FACS-sorted in vitro differentiated TMem samples were without stimulation (0 hours) (n=3), and FACS-sorted in vitro differentiated TMem samples were stimulated using CD3-specific and CD28-specific antibodies and IL-2 for 18 (n=3) and 96 (n=3) hours. FACS-sorted naive Pmel-1 CD8+ T cell samples were without stimulation (0 hours) (n=3), and FACS-sorted TN-derived Pmel-1 CD8+ T cell samples were stimulated using CD3-specific and CD28-specific antibodies and IL-2 for 18 (n=3) and 96 (n=3) hours. FACS-sorted TN-derived Pmel-1 CD8+ T cell samples were stimulated in the presence of TMem using CD3-specific and CD28-specific antibodies and IL-2 for 18 (n=3) and 96 (n=3) hours. FACS-sorted in vitro differentiated TMem samples were stimulated in the presence of TN using CD3-specific and CD28-specific antibodies and IL-2 for 18 (n=3) and 96 (n=3) hours. All samples were done in triplicate as biological repeats.

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CD27 costimulation modulates naïve T cell activation through TRAF2/SHP-1 and induces memory-associated gene regulatory networks.

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