title: PD-1 suppresses protective immunity to Streptococcus pneumoniae through a B cell-intrinsic mechanism.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27157;
authors.forename: Jerome T
authors.initials: JT
authors.lastname: McKay
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27157;
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Egan
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27157;
authors.forename: Rama D
authors.initials: RD
authors.lastname: Yammani
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519;
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.affiliation: Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; and.
authors.forename: Tahiro
authors.initials: T
authors.lastname: Shin
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27157; kmhaas@wakehealth.edu.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Haas
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis*; D001402:B-Lymphocytes / Q000276:immunology* / Q000382:microbiology; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D056724:Immunity, Humoral / Q000187:drug effects; D007114:Immunization; D007074:Immunoglobulin G / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011008:Pneumococcal Infections / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D022242:Pneumococcal Vaccines / Q000008:administration & dosage*; D011135:Polysaccharides, Bacterial / Q000008:administration & dosage; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000276:immunology; D016019:Survival Analysis
chemical_list: D000907:Antibodies, Bacterial; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D007074:Immunoglobulin G; C491383:Pdcd1 protein, mouse; D022242:Pneumococcal Vaccines; D011135:Polysaccharides, Bacterial; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor