T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition

Area of Science:

• Immunology
• Cancer Biology
• Molecular Signaling

Background:

• Programmed cell death-1 (PD-1) is a key coinhibitory receptor on T cells.
• PD-1 signaling, upon binding its ligand PD-L1, is known to suppress T cell activation.
• The precise molecular targets of PD-1-mediated suppression, particularly concerning T cell receptor (TCR) and co-receptor signaling, remain incompletely understood.

Purpose of the Study:

• To elucidate the specific molecular targets of PD-1 signaling in T cells.
• To determine whether PD-1-recruited phosphatases target the TCR or co-receptors like CD28.
• To understand the role of CD28 dephosphorylation in PD-1-mediated T cell suppression and immunotherapy.

Main Methods:

• Biochemical reconstitution system to precisely control and measure PD-1 signaling.
• Titration of PD-1 signaling components to assess phosphatase activity.
• Intact cell-based assays to validate findings in a physiological context.
• Phosphorylation analysis of TCR and CD28 following PD-1/PD-L1 engagement.

Main Results:

• PD-1-recruited Shp2 phosphatase preferentially dephosphorylates the CD28 co-receptor over the TCR.
• This preferential dephosphorylation of CD28 by PD-1 occurs in both reconstituted biochemical systems and intact T cells.
• TCR signaling remains largely unaffected, while CD28 signaling is significantly inhibited by PD-1 activation.

Conclusions:

• PD-1 primarily suppresses T cell function by inactivating CD28 signaling, rather than TCR signaling.
• This finding highlights the critical role of CD28 costimulation in effector T cell function.
• Understanding this mechanism provides new insights into the efficacy of anti-PD-1/PD-L1 cancer immunotherapies and suggests potential strategies for enhancement.