Requirement for CD40/CD40L Interactions for Development of Autoimmunity Differs Depending on Specific Checkpoint and...

Area of Science:

• Immunology
• Autoimmunity research
• Molecular biology

Background:

• CD40/CD40L interactions are crucial for immune responses and autoimmunity.
• Programmed cell death-1 (PD-1) and CD28 are key regulators of peripheral tolerance.
• Disruptions in these pathways can lead to loss of self-tolerance and autoimmune diseases.

Purpose of the Study:

• To investigate the role of CD40 signaling in autoimmune pathogenesis within PD-1 and CD28 pathways.
• To determine the necessity of CD40 signaling for autoimmune disease development in specific mouse models.
• To understand how PD-1 and CD28 availability influences the efficacy of CD40L blockade.

Main Methods:

• Utilized CD28-deficient and PD-1-deficient mouse models (IFN-γ^-/- NOD.H-2h4).
• Administered anti-CD40L mAb (MR1) to block CD40/CD40L interactions.
• Administered anti-PD-1 mAb in CD28-deficient mice.
• Assessed autoantibody production, inflammation in target tissues (thyroid, salivary glands), and splenic germinal centers.

Main Results:

• CD40 signaling was required for spontaneous Sjögren's syndrome (pSS) and autoimmune thyroid diseases (ATDs) in CD28-deficient mice.
• Anti-CD40L (MR1) treatment inhibited autoantibody production and inflammation in CD28-deficient mice.
• Autoimmunity in PD-1-deficient mice developed independently of CD40/CD40L interactions.
• Anti-CD40L treatment exacerbated disease in PD-1-deficient mice and increased specific autoantibodies.
• Blocking PD-1 in CD28-deficient mice mimicked the PD-1-deficient phenotype, rendering anti-CD40L therapy ineffective.

Conclusions:

• Autoimmune pathogenesis pathways differ based on the presence of specific costimulatory and checkpoint receptors.
• An intact PD-1 pathway is necessary for anti-CD40L therapy to suppress autoimmunity.
• CD40 signaling requirements vary depending on the status of PD-1 and CD28 pathways.