PD-1 suppresses protective immunity to Streptococcus pneumoniae through a B cell-intrinsic mechanism

• Published in: The Journal of immunology (1950) Vol. 194; no. 5; pp. 2289 - 2299
• Main Authors: McKay, Jerome T, Egan, Ryan P, Yammani, Rama D, Chen, Lieping, Shin, Tahiro, Yagita, Hideo, Haas, Karen M
• Format: Journal Article
• Language: English
• Published: United States 01-03-2015
• Subjects: Animals; Antibodies, Bacterial - biosynthesis; B-Lymphocytes - immunology; B-Lymphocytes - microbiology; B7-H1 Antigen - genetics; B7-H1 Antigen - immunology; Gene Expression Regulation; Immunity, Humoral - drug effects; Immunization; Immunoglobulin G - biosynthesis; Mice; Mice, Inbred C57BL; Mice, Knockout; Pneumococcal Infections - genetics; Pneumococcal Infections - immunology; Pneumococcal Infections - mortality; Pneumococcal Infections - prevention & control; Pneumococcal Vaccines - administration & dosage; Polysaccharides, Bacterial - administration & dosage; Programmed Cell Death 1 Ligand 2 Protein - genetics; Programmed Cell Death 1 Ligand 2 Protein - immunology; Programmed Cell Death 1 Receptor - deficiency; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; Signal Transduction; Streptococcus pneumoniae; Streptococcus pneumoniae - immunology; Survival Analysis
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1401673

Despite the emergence of the programmed cell death 1 (PD-1):PD-1 ligand (PD-L) regulatory axis as a promising target for treating multiple human diseases, remarkably little is known about how this pathway regulates responses to extracellular bacterial infections. We found that PD-1(-/-) mice, as well as wild-type mice treated with a PD-1 blocking Ab, exhibited significantly increased survival against lethal Streptococcus pneumoniae infection following either priming with low-dose pneumococcal respiratory infection or S. pneumoniae-capsular polysaccharide immunization. Enhanced survival in mice with disrupted PD-1:PD-L interactions was explained by significantly increased proliferation, isotype switching, and IgG production by pneumococcal capsule-specific B cells. Both PD-L, B7-H1 and B7-DC, contributed to PD-1-mediated suppression of protective capsule-specific IgG. Importantly, PD-1 was induced on capsule-specific B cells and suppressed IgG production and protection against pneumococcal infection in a B cell-intrinsic manner. To our knowledge, these results provide the first demonstration of a physiologic role for B cell-intrinsic PD-1 expression in vivo. In summary, our study reveals that B cell-expressed PD-1 plays a central role in regulating protection against S. pneumoniae, and thereby represents a promising target for bolstering immunity to encapsulated bacteria.