Immunomodulatory Role of NK Cells during Antiviral Antibody Therapy

Abstract

Monoclonal antibodies (mAbs) are now considered as a therapeutic approach to prevent and treat severe viral infections. Using a mouse retroviral model, we showed that mAbs induce protective immunity (vaccinal effects). Here, we investigated the role of natural killer (NK) cells on this effect. NK cells are effector cells that are crucial to control viral propagation upon mAb treatment. However, their immunomodulatory activity during antiviral mAb immunotherapies has been little studied. Our data reveal that the mAb treatment of infected mice preserves the functional activation of NK cells. Importantly, functional NK cells play an essential role in preventing immune dysfunction and inducing antiviral protective immunity upon mAb therapy. Thus, NK cell depletion in mAb-treated, viral-infected mice leads to the upregulation of molecules involved in immunosuppressive pathways (i.e., PD-1, PD-L1 and CD39) on dendritic cells and T cells. NK cell depletion also abrogates the vaccinal effects induced by mAb therapy. Our data also reveal a role for IFNγ-producing NK cells in the enhancement of the B-cell responses through the potentiation of the B-cell helper properties of neutrophils. These findings suggest that preserved NK cell functions and counts might be required for achieving mAb-induced protective immunity. They open new prospects for improving antiviral immunotherapies.

Differential and sequential immunomodulatory role of neutrophils and Ly6Chi inflammatory monocytes during antiviral antibody therapy

“…These data suggest that FcγRIV is not crucial to control the viral spread in infected/treated animals. They are consistent with our previous work showing that NK cells (that do not express FcγRIV) are key in controlling viral propagation by 667 mAb–mediated ADCC [ 18 , 34 ], while FcγRIV-expressing neutrophils have a limited effect on viral propagation in infected/treated mice but are crucial for the generation of long-term protective humoral responses [ 18 ]. Based on these observations, we assessed the effect of FcγRIV-blocking on the magnitude and quality of the humoral immune response in infected/treated mice.…”

“…Interestingly, mice that were not protected by 667 mAb treatment ( Figure 7 A) showed low levels of anti-FrCasE IgGs ( Figure 7 C and D). In contrast, the reduced percentage of mice that survived, showed a higher antiviral humoral response than unprotected mice ( Figure 7 C and D), consistently with the correlation between anti-FrCasE IgG serum levels and long-term protection we previously reported [ 18 , 34 ]. Furthermore, the lack of protection in infected/treated mice upon FcγRIV-blocking was also associated with a low IgG2a/IgG1ratio (< 0,5).…”

Fc-Dependent Immunomodulation Induced by Antiviral Therapeutic Antibodies: New Perspectives for Eliciting Protective Immune Responses

“… NK cells, in addition to their role in the elimination of infected cells, also have a key immunomodulatory role in the induction of a protective immune response after mAb treatment. This was demonstrated using an NK depletion approach that led to the abrogation of the vaccinal effects induced by mAb therapy (i.e., decreased virus-specific antibody titers and CD8 + T cell responses) [ 18 ]. The immunomodulatory effects of NK cells are two-fold.…”

“…Firstly, control of viral propagation by NK cells prevents immune cell exhaustion and the establishment of immunosuppressive mechanisms (i.e., upregulation of molecules involved in immunosuppressive pathways, such as PD-1, PD-L1, and CD39 on dendritic cells and T cells). Secondly, IFNγ-producing NK cells play a role in the enhancement of the B cell responses through the potentiation of the B cell helper properties of neutrophils [ 18 ].…”

New Advances in Nanomaterial‐Based Antiviral Strategies

“…However, toxicity, side effects, short half‐life, and low delivery efficiency of mAbs limit their clinical applications. [ 87 ] Using nanomaterials to deliver therapeutic antiviral mAbs may overcome these limitations. Biodegradable PLGA NPs loaded with mAbs possessing nucleic acid‐hydrolyzing activity against VSV showed high efficacy in the delivery of mAbs to the cytoplasmic region.…”