Induction of Type I Interferons by Therapeutic Nanoparticle-Based Vaccination Is Indispensable to Reinforce Cytotoxic CD8+ T Cell Responses During Chronic Retroviral Infection

Abstract

T cell dysfunction and immunosuppression are characteristic for chronic viral infections and contribute to viral persistence. Overcoming these burdens is the goal of new therapeutic strategies to cure chronic infectious diseases. We recently described that therapeutic vaccination of chronic retrovirus infected mice with a calcium phosphate (CaP) nanoparticle (NP)-based vaccine carrier, functionalized with CpG and viral peptides is able to efficiently reactivate the CD8+ T cell response and improve the eradication of virus infected cells. However, the mechanisms underlying this effect were largely unclear. While type I interferons (IFNs I) are considered to drive T cell exhaustion by persistent immune activation during chronic viral infection, we here describe an indispensable role of IFN I induced by therapeutic vaccination to efficiently reinforce cytotoxic CD8+ T cells (CTL) and improve control of chronic retroviral infection. The induction of IFN I is CpG dependent and leads to significant IFN signaling indicated by upregulation of IFN stimulated genes. By vaccinating chronically retrovirus-infected mice lacking the IFN I receptor (IFNAR−/−) or by blocking IFN I signaling in vivo during therapeutic vaccination, we demonstrate that IFN I signaling is necessary to drive full reactivation of CTLs. Surprisingly, we also identified an impaired suppressive capability of regulatory T cells in the presence of IFNα, which implicates an important role for vaccine-induced IFNα in the regulation of the T cell response during chronic retroviral infection. Our data suggest that inducing IFN I signaling in conjunction with the presentation of viral antigens can reactivate immune functions and reduce viral loads in chronic infections. Therefore, we propose CaP NPs as potential therapeutic tool to treat chronic infections.

Effective Activation of Human Antigen-Presenting Cells and Cytotoxic CD8+ T Cells by a Calcium Phosphate-Based Nanoparticle Vaccine Delivery System

“…This is well in line with our previous results from mouse models and could be due to the enhanced delivery of the ligands to endosomal compartments, where TLR 3 and TLR 9 are located [16,20]. IL-12, IL-2, IFN-α, and TNFα are very important for the sufficient activation of effector CD8 + T cells [19,[31][32][33] or in an autocrine manner for enhanced DC function [34]. Therefore, this is an optimal prerequisite for effective T cell priming.…”

“…Therefore, analysis at an earlier time point might show stronger differences regarding costimulatory molecule expression. Concentrations of the TLR ligands were adjusted from in vivo data that was generated previously [17,19]. Lower concentrations of NPs or TLR ligands might also emphasize the advantage of CaP NPs.…”

“…Encapsulation of these ligands into NPs could further improve this effect. Previously, we described the efficient uptake of CpG functionalized CaP nanoparticles by and activation of DCs in mouse models, which results in enhanced activation of CD8 + effector T cell responses [17][18][19]. CD8 + T cells gained activation and expression of effector molecules such as IFNγ or granzyme B, which leads to repressed tumor growth or enhanced elimination of virus-infected cells.…”

A Tumor-Peptide–Based Nanoparticle Vaccine Elicits Efficient Tumor Growth Control in Antitumor Immunotherapy

“…Recently, we have demonstrated that reactivation of virusspecific CD8 þ T cells with functionalized CaP nanoparticles is dependent on IFN I during therapeutic vaccination of chronically infected mice (24). In this study, CpG was identified as driving force of IFN I release.…”

Friend retrovirus studies reveal complex interactions between intrinsic, innate and adaptive immunity

“…Nanoparticle vaccines delivering FV antigen and molecules for TLR stimulation were able to induce potent T cell responses that restricted chronic FV infection (Knuschke et al 2014). This successful therapeutic vaccination was dependent on type I IFN induction (Knuschke et al 2018) and could be further improved by Treg depletion (Knuschke et al 2016).…”