The programmed death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo

Area of Science:

• Immunology
• Autoimmunity
• Diabetes Research

Background:

• Programmed death-1 ligand 1 (PD-L1) is a key coinhibitory molecule regulating immune tolerance.
• PD-L1's role in type 1 diabetes development in NOD mice is established, but the significance of its interaction with B7-1 is unclear.

Purpose of the Study:

• To investigate the specific role of the PD-L1:B7-1 interaction in regulating self-reactive T cell responses in the NOD mouse model of diabetes.
• To compare the in vivo effects of blocking PD-L1:B7-1 interactions versus blocking both PD-L1:B7-1 and PD-L1:programmed death-1 interactions.

Main Methods:

• Utilized two anti-PD-L1 monoclonal antibodies (mAbs) with distinct blocking activities: 10F.2H11 (blocks PD-L1:B7-1 only) and 10F.9G2 (blocks both PD-L1:B7-1 and PD-L1:programmed death-1).
• Administered mAbs to NOD mice of different ages and assessed diabetes acceleration.
• Investigated effects in adoptive transfer models using T cells from diabetic and prediabetic NOD mice.
• Examined the impact on both CD4(+) and CD8(+) T cell-driven diabetes.

Main Results:

• Both anti-PD-L1 mAbs accelerated diabetes in NOD mice, but with distinct age-dependent effects.
• The single-blocker (10F.2H11) was more effective in older mice, while the dual-blocker (10F.9G2) rapidly induced diabetes in mice of all tested ages.
• 10F.9G2 accelerated diabetes in recipients of T cells from both diabetic and prediabetic mice, whereas 10F.2H11 was effective only with diabetic T cells.
• Both mAbs precipitated diabetes in CD4(+) and CD8(+) T cell transfer models.

Conclusions:

• The PD-L1:B7-1 pathway plays a significant role in inhibiting potentially pathogenic self-reactive CD4(+) and CD8(+) T cell responses in vivo.
• The immunoinhibitory function of the PD-L1:B7-1 pathway appears particularly crucial during the later stages of autoimmune diabetes development (diabetogenesis).