An integrin-associated protein CD47, which is a ligand for the inhibitory receptor signal regulatory protein α, is expressed on B and T cells as well as on most innate immune cells. However, the roles of CD47 in the immune responses to viral infection or vaccination remain unknown. We have investigated the role of CD47 in inducing humoral immune responses after intranasal infection with virus or immunization with influenza virus-like particles (VLP). Virus infection or vaccination with VLP containing hemagglutinin (HA) from A/PR8/34 influenza virus induced higher levels of antigen-specific IgG2c isotype dominant antibodies in CD47-deficient (CD47KO) mice than those in wild type (WT) mice. CD47KO mice with vaccination showed higher protective efficacy against lethal challenge, as evidenced by no loss in body weight and reduced lung viral titers compared to WT mice. In addition, inflammatory responses which include cytokine production, leukocyte infiltrates, and interferon gamma (IFN-γ)-producing CD4⁺ T cells as well as anti-inflammatory cytokine (IL-10) were reduced in the lung of vaccinated CD47KO mice after challenge with influenza virus. Analysis of lymphocytes indicated that GL7⁺ germinal center B cells were induced at higher levels in the draining lymph nodes of CD47KO mice as compared with those in WT mice. Notably, CD47KO mice exhibited significant increases in the numbers of antigen-specific memory B cells in spleens and plasma cells in bone marrow despite their lower levels of background IgG antibodies. Thus, these results suggest that CD47 plays a role as a negative regulator in inducing protective immune responses to influenza vaccination.

IMPORTANCE:

Molecular mechanisms that control B cell activation to produce protective antibodies upon viral vaccination remain poorly understood. The CD47 molecule is known to be a ligand for the inhibitory receptor signal regulatory protein α and expressed on the surfaces of most immune cell types. CD47 was previously demonstrated to play an important role in modulating the migration of monocytes, neutrophils, polymorphonuclear neutrophils, and dendritic cells into the inflamed tissues. Results in this study demonstrate new roles of CD47 in negatively regulating the induction of protective IgG antibodies, germinal center B cells, and plasma cells secreting antigen-specific antibodies as well as macrophages upon influenza vaccination and challenge. As consequences, vaccinated CD47 deficient mice resulted in better control of influenza viral infection and enhanced protection. This study provides insights into understanding the regulatory functions of CD47 in inducing adaptive immunity to vaccination.