Type I Interferons Modulate CD8 + T Cell Immunity to mRNA Vaccines

Antigen-encoding mRNA vaccines (e.g., against tumors) exhibit a high capacity to elicit cytolytic CD8+ T cells, with a unique capacity to destroy cancer (or virally infected) cells. mRNA vaccines elicit a profound type of I IFN response and specific signature. Type I IFNs can have either a beneficial or a detrimental impact on CD8+ T cell immunity. Type I IFNs can promote CD8+ T cell responses to systemic mRNA vaccination yet interfere with topical (intradermal/subcutaneous) mRNA vaccination. The functional repercussions of type I IFNs on the magnitude and quality of elicited CD8+ T cell responses are a topic of intense debate. The dual effects of type I IFNs on antiviral CD8+ T cell immunity are largely determined by the relative kinetics of type I IFN signaling to T cell receptor (TCR) activation. Based on these findings, we argue that similar mechanisms govern the impact of type I IFNs on the CD8+ T cell response to mRNA vaccines. mRNA vaccines have emerged as potent tools to elicit antitumor T cell immunity. They are characterized by a strong induction of type I interferons (IFNs), potent inflammatory cytokines affecting T cell differentiation and survival. Recent reports have attributed opposing roles for type I IFNs in modulating CD8+ T cell immunity to mRNA vaccines, from profoundly stimulatory to strongly inhibitory. The mechanisms behind this duality are unclear. Disentangling the factors governing the beneficial or detrimental impact of type I IFNs on CD8+ T cell responses is vital to the design of mRNA vaccines of increased potency. In light of recent advancements regarding the complex role of type I IFNs in regulating CD8+ T cell immunity to infectious diseases, we posit that the dual outcome of type I IFNs on CD8+ T cell responses to mRNA vaccination is determined by the timing and intensity of type I IFN induction relative to T cell receptor (TCR) activation. mRNA vaccines have emerged as potent tools to elicit antitumor T cell immunity. They are characterized by a strong induction of type I interferons (IFNs), potent inflammatory cytokines affecting T cell differentiation and survival. Recent reports have attributed opposing roles for type I IFNs in modulating CD8+ T cell immunity to mRNA vaccines, from profoundly stimulatory to strongly inhibitory. The mechanisms behind this duality are unclear. Disentangling the factors governing the beneficial or detrimental impact of type I IFNs on CD8+ T cell responses is vital to the design of mRNA vaccines of increased potency. In light of recent advancements regarding the complex role of type I IFNs in regulating CD8+ T cell immunity to infectious diseases, we posit that the dual outcome of type I IFNs on CD8+ T cell responses to mRNA vaccination is determined by the timing and intensity of type I IFN induction relative to T cell receptor (TCR) activation. exogenous and endogenous antigens are presented by antigen-presenting cells (APCs) via major histocompatibility complex-I (MHC-I) or -II to CD8+ T cells or CD4+ T cells, respectively. Class I MHC molecules occur on all nucleated cells and present peptides generated in the cytosol, whereas Class II MHC molecules are largely restricted to APCs and present peptides following the endocytic pathway. the cell enters a phase in which an internal death program has been started. This noninflammatory process is characterized by nuclear condensation and fragmentation and plasma membrane permeabilization, subsequently resulting in phagocytosis. nonmigrating resident DCs that efficiently cross-present exogenous cell-bound and soluble antigens on MHC-I. In an activated form, they are major producers of inflammatory cytokines and outperform other subsets in presenting pathogenic antigens. a cytokine expressed on activated T and B lymphocytes that interacts with the CD27 receptor. CD70-CD27 signaling induces T and B cell activation and contributes to the generation of cytolytic T cells and natural killer (NK) cells. as part of DC maturation, the expression of co-stimulatory ligands (CD80, CD86, and CD70) is upregulated. These ligands bind to their receptor on the T cell surface to promote the cell cycle activity, survival, and differentiation of effector and memory T cells. unmethylated 5′-cytosine-phosphate-guanine-3′ or ‘CpG motifs’ are DNA regions typically present in bacterial DNA; they trigger TLR9 receptors to mount an innate immune response characterized by the production of Th1-related proinflammatory cytokines. the presentation of exogenous antigens by MHC-I complexes to CD8+ T cells (rather than conventional MHC-II presentation to CD4+ T cells). an immune response in which the main effector function constitutes the killing of virally infected cells or tumor cells using cytotoxic cell granules. CD8+ T cells differentiate into cytolytic effector CD8+ T cells upon MHC-I-mediated antigen presentation in the presence of IL-12 and type I IFNs. mRNA nanoparticles comprising mRNA-encoding antigens and the 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) with the helper lipid 1,2-dioleoyl sn-glycerol-3-phosphoethanolamine (DOPE). mRNA nanoparticles comprising mRNA-encoding antigens and two lipids: 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA) and 1,2-dioleoyl sn-glycerol-3-phosphoethanolamine (DOPE). lipid-mediated nanoparticles that formulate mRNA encoding the HIV1-related group-specific polyproteins (Gag), including six proteins: MA, CA, NC, SP1, SP2, and P6. produced via an RNA polymerase-based reaction starting from a DNA template vector, which contains a RNA polymerase-specific promoter, 3′ and 5′ untranslated regions (UTRs), a gene-coding sequence, and a poly(A) tail. encompasses a broad panel of different therapeutic molecules, such as antibodies, proteins, cytokines, and so on. Immunotherapy is used to treat a given disease by stimulating and strengthening the patient’s own immune system. in general, lipoplexes are lipid-based formulations of nucleic acids encoding antigens. Lipoplexes are spherical structures with a diameter in the range of 100 nm. They protect nucleic acids in vivo and facilitate entry into cells. a form of actin-dependent endocytosis that mediates nonselective uptake of molecules. This uptake process gives rise to large endocytic vacuoles called macropinosomes. artificial vesicles comprising lipids and mRNA, forming phospholipid bilayers in the nanometer range. mRNA lipoplexes are used for the delivery of mRNA as vaccines or therapeutics. have an important role in innate immunity by detecting pathogens via the identification of highly conserved pathogen-associated molecular patterns (PAMPS) and endogenous danger-associated molecular patterns (DAMPs), secreted from necrotic cells. These receptors are mainly expressed by APCs, although are also expressed by other immune and non-immune cells. the surface of mRNA nanoparticles can be coated with polyethylene glycol (PEG) to create a PEG-based sheath around mRNA nanocomplexes. They are used to reduce the adhesive interaction of serum proteins and intracellular components with mRNA nanoparticles. a subset of DCs specialized in the recognition of pathogenic nucleic acids and the production of type I IFNs upon activation. pDCs have major functions in infection, autoimmunity, and cancer. comprise two components, mRNA complexed to protamine and naked mRNA that encodes the antigen of interest. RNActive vaccines have self-adjuvating properties and allow the expression of the antigenic target protein, while simultaneously providing a strong danger signal leading to the activation of TLRs. lipofectamine reagent used to transfect cells in vitro and to deliver RNA-encoding antigen in vivo. the activation of CD8+ T cells appears to require three signals: TCR engagement (signal 1), co-stimulation (signal 2), and an inflammatory stimulus (signal 3). The third signal that determines the functionality of the evoked CD8 + T cells is achieved via the secretion of certain cytokines. Type I IFNs and IL-12 are key signal 3 cytokines that govern the differentiation of CD8+ T cells into IFN-γ secreting and cytolytic effector cells. TCR activation that promotes several signaling cascades and determines cell fate through the regulation of cytokine production. TCR signaling is initiated when the TCR-CD3 complex binds the composite surface of peptides embedded in MHC-I/II molecules. 12 murine and ten human TLRs have been characterized so far. Each TLR receptor interacts with a specific agonist, such as viral RNA or DNA, lipopolysaccharides, bacterial flagellin, or unmethylated CpG DNA motifs. In addition, small synthetic molecules, such as imidazoquinolines, can be designed to activate TLRs.