CD40 ligand has potent antiviral activity

IFN-β and the CD40L (CD154) share important roles in the antiviral and antitumor immune responses. In this study, we show that CD40 receptor occupancy results in IFN-β upregulation through an unconventional “feed-forward” mechanism, which is orchestrated by canonical NF-κB and involves the sequential de novo synthesis of IFN regulatory factor (IRF)1 and Viperin (RSAD2), an IRF1 target. RelA (p65) NF-κB, IRF1, and Viperin-dependent IRF7 binding to the IFN-β promoter largely controls its activity. However, full activation of IFN-β also requires the parallel engagement of noncanonical NF-κB2 signaling leading to p52 recruitment to the IFN-β promoter. These data define a novel link between CD40 signaling and IFN-β expression and provide a telling example of how signal propagation can be exploited to ensure efficient regulation of gene expression.

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

CD40 Stimulates a “Feed-Forward” NF-κB–Driven Molecular Pathway That Regulates IFN-β Expression in Carcinoma Cells

Moschonas

Ioannou

Eliopoulos

2012

“…However, endogenous IFN-␥ production is not crucial for control of VV replication. Interestingly, studies with recombinant VV vectors expressing IL-2 (86), TNF-␣ (87), CD40L (88), and NOS2 (40) have all suggested a critical role for these factors in resistance to VV. However, mice deficient for these genes cleared VV normally (28,57,89) (Fig.…”

Section: Discussionmentioning

confidence: 99%

IL-4 and IL-10 Antagonize IL-12-Mediated Protection Against Acute Vaccinia Virus Infection with a Limited Role of IFN-γ and Nitric Oxide Synthetase 2

Broek¹,

Bachmann²,

Köhler

et al. 2000

126

Resistance or susceptibility to most infectious diseases is strongly determined by the balance of type 1 vs type 2 cytokines produced during infection. However, for viruses, this scheme may be applicable only to infections with some cytopathic viruses, where IFN-γ is considered as mandatory for host defense with little if any participation of type 2 responses. We studied the role of signature Th1 (IL-12, IFN-γ) and Th2 (IL-4, IL-10) cytokines for immune responses against vaccinia virus (VV). IL-12−/− mice were far more susceptible than IFN-γ−/− mice, and primary CTL responses against VV were absent in IL-12−/− mice but remained intact in IFN-γ−/− mice. Both CD4+ and CD8+ T cells from IL-12−/− mice were unimpaired in IFN-γ production, although CD4+ T cells showed elevated Th2 cytokine responses. Virus replication was impaired in IL-4−/− mice and, even more strikingly, in IL-10−/− mice, which both produced elevated levels of the proinflammatory cytokines IL-1α and IL-6. Thus, IL-4 produced by Th2 cells and IL-10 produced by Th2 cells and probably also by macrophages counteract efficient anti-viral host defense. Surprisingly, NO production, which is considered as a major type 1 effector pathway inhibited by type 2 cytokines, appears to play a limited role against VV, because NO sythetase 2-deficient mice did not show increased viral replication. Thus, our results identify a new role for IL-12 in defense beyond the induction of IFN-γ and show that IL-4 and IL-10 modulate host protective responses to VV.

“…Immunization of BALB/c mice with DNA plasmids expressing ␤-galactosidase and CD40L increased the Th1-type immune response to ␤-galactosidase (51). Infection of mice with recombinant vaccinia virus that expressed CD40L markedly enhanced viral clearance by both an IFN-␥-dependent mechanism and a novel CD40L-dependent mechanism (64). Administering anti-CD40 mAb to mice together with pneumococcal polysaccharide generated strong, isotypeswitched Ab responses (67).…”

Section: Discussionmentioning

confidence: 99%

CD40 Ligand (CD154) Enhances the Th1 and Antibody Responses to Respiratory Syncytial Virus in the BALB/c Mouse

Tripp

Jones

Anderson

et al. 2000

CD40 ligand (CD40L) is a cell surface costimulatory molecule expressed mainly by activated T cells. CD40L is critically important for T-B cell and T cell-dendritic cell interactions. CD40L expression promotes Th1 cytokine responses to protein Ags and is responsible for Ig isotype switching in B cells. Respiratory syncytial virus (RSV) is an important pathogen of young children and the elderly, which causes bronchiolitis and pneumonia. Studies of mice infected with RSV suggest that a Th2 cytokine response may be responsible for enhanced pulmonary disease. To investigate the effect CD40L has on RSV immunity, mice were infected simultaneously with RSV and either an empty control adenovirus vector or one expressing CD40L or were coimmunized with plasmid DNA vectors expressing CD40L and RSV F and/or G proteins and subsequently challenged with RSV. The kinetics of the intracellular and secreted cytokine responses, the cytotoxic T lymphocyte precursor frequency, NO levels in lung lavage, rates of virus clearance, and anti-RSV Ab titers were determined. These studies show that coincident expression of CD40L enhances the Th1 (IL-2 and IFN-γ) cytokine responses, increases the expression of TNF-α and NO, accelerates virus clearance, and increases the anti-F and anti-G Ab responses. These data suggest that CD40L may have the adjuvant properties needed to optimize the safety and efficacy of RSV vaccines.