PD-1 blockade exacerbates Mycobacterium tuberculosis infection in rhesus macaques

Area of Science:

• Immunology
• Infectious Diseases
• Microbiology

Background:

• Coinhibitory receptor PD-1 plays a role in regulating immune responses during chronic infections.
• Targeting PD-1 is being explored for therapeutic applications in treating persistent infections.

Purpose of the Study:

• To investigate the role of PD-1 during Mycobacterium tuberculosis (Mtb) infection in a rhesus macaque model.
• To determine the impact of PD-1 blockade on immune cell function and disease progression in tuberculosis.

Main Methods:

• Rhesus macaques infected with Mtb were treated with anti-PD-1 monoclonal antibody or an isotype control.
• Immune cell populations (CD4+ and CD8+ T cells) and cytokine levels within granulomas were analyzed.
• Intralesional trafficking of T cells was assessed using live imaging.
• The association between intestinal microbiota composition and disease outcome was examined.

Main Results:

• Anti-PD-1 treatment led to exacerbated disease and higher bacterial loads in granulomas.
• PD-1 blockade enhanced the number and function of Mtb-specific CD8+ T cells but not CD4+ T cells.
• CD4+ T cells in anti-PD-1 treated macaques showed increased CTLA-4 expression and reduced trafficking.
• Elevated proinflammatory cytokines and a role for caspase-1 in disease exacerbation were identified.
• Increased Mtb bacterial loads correlated with pre-infection intestinal microbiota composition.

Conclusions:

• PD-1-mediated coinhibition is essential for controlling Mtb infection in macaques.
• PD-1 blockade may worsen tuberculosis by promoting detrimental inflammation and impairing CD4+ T cell responses.
• The intestinal microbiota may influence the outcome of PD-1 blockade therapy in Mtb infection.