title: Downmodulation of vaccine-induced immunity and protection against the intracellular bacterium Francisella tularensis by the inhibitory receptor FcγRIIB.
abstract: Fc gamma receptor IIB (FcγRIIB) is the only Fc gamma receptor (FcγR) which negatively regulates the immune response, when engaged by antigen- (Ag-) antibody (Ab) complexes. Thus, the generation of Ag-specific IgG in response to infection or immunization has the potential to downmodulate immune protection against infection. Therefore, we sought to determine the impact of FcγRIIB on immune protection against Francisella tularensis (Ft), a Category A biothreat agent. We utilized inactivated Ft (iFt) as an immunogen. Naïve and iFt-immunized FcγRIIB knockout (KO) or wildtype (WT) mice were challenged with Ft-live vaccine strain (LVS). While no significant difference in survival between naïve FcγRIIB KO versus WT mice was observed, iFt-immunized FcγRIIB KO mice were significantly better protected than iFt-immunized WT mice. Ft-specific IgA in serum and bronchial alveolar lavage, as well as IFN-γ, IL-10, and TNF-α production by splenocytes harvested from iFt-immunized FcγRIIB KO, were also significantly elevated. In addition, iFt-immunized FcγRIIB KO mice exhibited a reduction in proinflammatory cytokine levels in vivo at 5 days after challenge, which correlates with increased survival following Ft-LVS challenge in published studies. Thus, these studies demonstrate for the first time the ability of FcγRIIB to regulate vaccine-induced IgA production and downmodulate immunity and protection. The immune mechanisms behind the above observations and their potential impact on vaccine development are discussed.
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Franz
authors.affiliation: Regeneron Pharmaceuticals, 81 Columbia Turnpike, Rensselaer, NY 12144, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Biological Sciences, Seton Hall University, South Orange, NJ 07079, USA.
authors.forename: Constantine
authors.initials: C
authors.lastname: Bitsaktsis
authors.affiliation: Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
authors.forename: Bibiana V
authors.initials: BV
authors.lastname: Iglesias
authors.affiliation: Pfizer, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Giang
authors.initials: G
authors.lastname: Pham
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Raju
authors.initials: R
authors.lastname: Sunagar
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Sudeep
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Gosselin
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood* / Q000276:immunology; D001428:Bacterial Vaccines / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016207:Cytokines / Q000097:blood; D005604:Francisella tularensis / Q000276:immunology*; D007070:Immunoglobulin A / Q000097:blood* / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017452:Receptors, IgG / Q000235:genetics* / Q000276:immunology*; D013154:Spleen / Q000166:cytology; D014406:Tularemia / Q000276:immunology / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D001428:Bacterial Vaccines; D016207:Cytokines; C499172:Fcgr2b protein, mouse; C508609:IL10 protein, human; C098680:Il17a protein, mouse; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D020381:Interleukin-17; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; D014613:Vaccines, Attenuated; D016753:Interleukin-10; D007371:Interferon-gamma