CD40 ligand preferentially modulates immune response and enhances protection against influenza virus.

Abstract

CD40L, a key regulator of the immune system, was studied as both a targeting ligand and a molecular adjuvant in nucleoprotein (NP)-based host defense against influenza in mouse models with different genetic backgrounds. Adenoviral vectors secreting NP-CD40L fusion protein (denoted as rAd-SNP40L) afforded full protection of immunocompetent and immunocompromised mice (CD40L(-/-) and CD4(-/-)) against lethal influenza infection. Mechanistically, rAd-SNP40L preferentially induced early and persistent B cell germinal center formation, and accelerated Ig isotype-switching and Th1-skewed, NP-specific Ab response. Moreover, it drastically augmented primary and memory NP-specific CTL activity and polyfunctional CD8(+) T cells. The markedly enhanced nonneutralizing Abs and CTLs significantly reduced viral burdens in the lungs of mice upon lethal virus challenge. Data generated from CD40L(-/-) and CD4(-/-) mice revealed that the protection was indeed CD40L mediated but CD4(+) T cell independent, demonstrating the viability of the fusion Ags in protecting immunodeficient hosts. Notably, a single dose of rAd-SNP40L completely protected mice from lethal viral challenge 4 mo after immunization, representing the first report, to our knowledge, on NP in conjunction with a molecular adjuvant inducing a robust and long-lasting memory immune response against influenza. This platform is characterized by an increased in vivo load of CD40-targeted Ag upon the secretion of the fusion protein from adenovirus-infected cells and may represent a promising strategy to enhance the breadth, durability, and potency of Ag-specific immune responses.

• Authors: Anwar M Hashem, Caroline Gravel, Ze Chen, Yinglei Yi, Monika Tocchi, Bozena Jaentschke, Xingliang Fan, Changgui Li, Michael Rosu-Myles, Alexander Pereboev, Runtao He, Junzhi Wang, Xuguang Li
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 193 Issue 2 Pg. 722-34 (Jul 15 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 24928989 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by The American Association of Immunologists, Inc.

Chemical References

• Nucleoproteins
• Recombinant Fusion Proteins
• CD40 Ligand

Topics

• Adaptive Immunity (genetics, immunology)
• Adenoviridae (genetics)
• Animals
• B-Lymphocytes (immunology, metabolism)
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• CD40 Ligand (deficiency, genetics, immunology)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Dogs
• Female
• Genetic Vectors (genetics)
• HEK293 Cells
• Humans
• Immunization
• Influenza A virus (immunology, physiology)
• Madin Darby Canine Kidney Cells
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• NIH 3T3 Cells
• Nucleoproteins (genetics, immunology, metabolism)
• Orthomyxoviridae Infections (genetics, immunology, virology)
• Recombinant Fusion Proteins (genetics, immunology, metabolism)
• Survival Analysis
• T-Lymphocytes, Cytotoxic (immunology)