PD-L2 is a second ligand for PD-1 and inhibits T cell activation

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Programmed death 1 (PD-1) is an inhibitory receptor vital for maintaining immune tolerance.
• PD-1-deficient mice exhibit autoimmune-like conditions, underscoring its regulatory role.
• The function and expression of PD-1 ligands, PD-L1 and PD-L2, are critical for understanding immune regulation.

Purpose of the Study:

• To identify and characterize a second ligand for PD-1, named PD-1 ligand 2 (PD-L2).
• To compare the functional and expression profiles of PD-L1 and PD-L2.
• To elucidate the role of PD-L-PD-1 interactions in T cell responses.

Main Methods:

• Investigated the inhibitory effects of PD-L2 engagement with PD-1 on T cell receptor (TCR)-mediated responses.
• Analyzed T cell proliferation and cytokine production under varying antigen concentrations.
• Examined cell cycle progression and SHP-2 phosphorylation upon PD-1 ligation.
• Assessed PD-L expression on antigen-presenting cells and various tissues.

Main Results:

• PD-L2 binding to PD-1 significantly inhibits TCR-mediated T cell proliferation and cytokine production.
• PD-L2-PD-1 interactions suppress T cell responses by inhibiting B7-CD28 co-stimulation at low antigen levels.
• At high antigen concentrations, PD-L2-PD-1 interactions reduce cytokine production but not proliferation.
• PD-L-PD-1 interactions induce G0/G1 cell cycle arrest without increasing cell death.
• PD-1 ligation combined with TCR stimulation rapidly phosphorylates SHP-2.
• PD-L expression is upregulated by interferon-gamma and found in normal tissues and tumor cell lines.

Conclusions:

• PD-L1 and PD-L2 exhibit overlapping functions in immune regulation.
• The PD-L-PD-1 pathway plays a critical role in modulating T cell responses.
• Understanding PD-L-PD-1 interactions is key to developing strategies for immune tolerance and therapeutic interventions.