Intestinal tolerance is converted to autoimmune enteritis upon PD-1 ligand blockade

Area of Science:

• Immunology
• Gastroenterology
• Autoimmunity

Background:

• Programmed death-1 ligand (PD-L1) regulates T cell responses.
• The role of PD-L1 in intestinal self-antigen (self-Ag) tolerance is unknown.
• CD8(+) T cells are critical for adaptive immunity.

Purpose of the Study:

• Investigate PD-L1's role in CD8(+) T cell tolerance to intestinal self-Ags.
• Utilize the iFABP-tOVA transgenic mouse model for intestinal self-Ag expression.
• Determine the consequences of PD-1:PD-L1 signaling loss in the gut.

Main Methods:

• Adoptive transfer of naive OVA-specific CD8(+) T cells.
• PD-L1 blockade using antibodies or transfer of PD-1(-/-) T cells.
• Analysis of T cell expansion, differentiation, cytokine production, and tissue damage.

Main Results:

• Loss of PD-1:PD-L1 signaling caused significant expansion of OVA-specific CD8(+) T cells.
• These T cells differentiated into effector cells producing proinflammatory cytokines.
• PD-1:PD-L1 blockade led to fatal CD8(+) T cell-mediated enteritis, epithelial barrier destruction, villi blunting, and myeloid cell recruitment.

Conclusions:

• PD-1:PD-L1 signaling is essential for maintaining CD8(+) T cell tolerance to intestinal self-Ags.
• Disruption of this pathway results in severe, organ-specific enteric autoimmunity.
• This highlights the PD-1:PD-L1 pathway as a critical regulator of gut immune homeostasis.