Spatiotemporal regulation of type I interferon expression determines the antiviral polarization of CD4+ T cells

Giovanni, Marco De; Cutillo, Valeria; Giladi, Amir; Sala, Eleonora; Maganuco, Carmela G.; Medaglia, Chiara; Lucia, Pietro Di; Bono, Elisa; Cristofani, Claudia; Consolo, Eleonora; Giustini, Leonardo; Fiore, Alessandra; Eickhoff, Sarah; Kastenmüller, Wolfgang; Kuka, Mirela; Iannacone, Matteo

doi:10.1038/s41590-020-0596-6

Cited by 73 publications

(121 citation statements)

References 62 publications

(76 reference statements)

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“…dose of vaccine, and boost vaccination with the identical virus in the same hind leg further boosted VNA activity to levels superior to those of COVID-19 patients. VSV infection is known to induce a strong Th1 biased antiviral and anticancer immune response (Bongiorno et al, 2017; De Giovanni et al, 2020). This holds also true for VSVΔG-minispike-eGFP vaccination, as indicated by preliminary results from rats.…”

Section: Discussionmentioning

confidence: 99%

Safe and effective two-in-one replicon-and-VLP minispike vaccine for COVID-19

Hennrich

Banda

Oberhuber

et al. 2020

Preprint

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The large SARS-CoV-2 spike (S) protein is the main target of current COVID-19 vaccine candidates but can induce non-neutralizing antibodies, which may cause vaccination-induced complications or enhancement of COVID-19 disease. Besides, encoding of a functional S in replication-competent virus vector vaccines may result in the emergence of viruses with altered or expanded tropism. Here, we have developed a safe single round rhabdovirus replicon vaccine platform for enhanced presentation of the S receptor-binding domain (RBD). Structure-guided design was employed to build a chimeric minispike comprising the globular RBD linked to a transmembrane stem-anchor sequence derived from rabies virus (RABV) glycoprotein (G). Vesicular stomatitis virus (VSV) and RABV replicons encoding the minispike not only allowed expression of the antigen at the cell surface but also incorporation into the envelope of secreted non-infectious particles, thus combining classic vector-driven antigen expression and particulate virus-like particle (VLP) presentation. A single dose of a prototype replicon vaccine, VSVΔG-minispike-eGFP (G), stimulated high titers of SARS-CoV-2 neutralizing antibodies in mice, equivalent to those found in COVID-19 patients. Boost immunization with the identical replicon further enhanced neutralizing activity. These results demonstrate that rhabdovirus minispike replicons represent effective and safe alternatives to vaccination approaches using replication-competent viruses and/or the entire S antigen.

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Section: Discussionmentioning

confidence: 99%

Safe and effective two-in-one replicon-and-VLP minispike vaccine for COVID-19

Hennrich

Banda

Oberhuber

et al. 2020

Preprint

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“…46 The impact of the distinct cytokine milieu in various viral infections was confirmed in a study that investigated the inflammatory cytokines that distinctly impact Tfh and Th1 differentiation during vesicular stomatitis virus and LCMV infection. 109 Taken together, these works propose that each viral infection elicits unique inflammatory cues that work independently or together to regulate transcriptional networks that promote either T-bet or Bcl6 and control the Th1/Tfh bifurcation (Fig. 3).…”

Section: Cytokine Mediators Of the Th1/tfh Dichotomy: Translating Infmentioning

confidence: 94%

“…In turn, this promoted precursor cells to commit to the Tfh fate at the expense of the Th1 fate. 109 In contrast, late production of type I IFN resulted in DCs becoming insensitive to type I IFN; hence, DCs failed to produce IL-6. In this setting, precursor cells adopted a Th1 fate trajectory instead of a Tfh trajectory.…”

Section: Il-6mentioning

confidence: 99%

“…In this setting, precursor cells adopted a Th1 fate trajectory instead of a Tfh trajectory. 109 Another study showed that activated follicular B cells also secrete IL-6 early in influenza infection, which is sufficient to drive Tfh differentiation. 114 In accordance with these findings, within GCs, follicular DCs produce IL-6 in the late stage of Tfh development.…”

Section: Il-6mentioning

confidence: 99%

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Transcription tipping points for T follicular helper cell and T-helper 1 cell fate commitment

Sheikh

Groom

2020

Cell Mol Immunol

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During viral infection, immune cells coordinate the induction of inflammatory responses that clear infection and humoral responses that promote protection. CD4+ T-cell differentiation sits at the center of this axis. Differentiation toward T-helper 1 (Th1) cells mediates inflammation and pathogen clearance, while T follicular helper (Tfh) cells facilitate germinal center (GC) reactions for the generation of high-affinity antibodies and immune memory. While Th1 and Tfh differentiation occurs in parallel, these CD4+ T-cell identities are mutually exclusive, and progression toward these ends is determined via the upregulation of T-bet and Bcl6, respectively. These lineage-defining transcription factors act in concert with multiple networks of transcriptional regulators that tip the T-bet and Bcl6 axis in CD4+ T-cell progenitors to either a Th1 or Tfh fate. It is now clear that these transcriptional networks are guided by cytokine cues that are not only varied between distinct viral infections but also dynamically altered throughout the duration of infection. Thus, multiple intrinsic and extrinsic factors combine to specify the fate, plasticity, and function of Th1 and Tfh cells during infection. Here, we review the current information on the mode of action of the lineage-defining transcription factors Bcl6 and T-bet and how they act individually and in complex to govern CD4+ T-cell ontogeny. Furthermore, we outline the multifaceted transcriptional regulatory networks that act upstream and downstream of Bcl6 and T-bet to tip the differentiation equilibrium toward either a Tfh or Th1 fate and how these are impacted by dynamic inflammatory cues.

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“…They used vesicular stomatitis virus (VSV), a cytopathic virus that induces potent neutralizing antibodies, and lymphocytic choriomeningitis virus (LCMV), a noncytopathic virus that elicits a robust cellular response. 4 Antigen-specific Tg7 or SMARTA CD4 + T cells were adoptively transferred prior to the infection of mice with VSV or LCMV, respectively. In VSV-infected mice, >40% of antigen-specific CD4 +…”

mentioning

confidence: 99%

Add on the next level—the time point of the type I IFN response orchestrates the immune response

2020

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The directed control of an effective cellular or adaptive immune response is the aim of vaccine strategies and tumor therapy. Neutralizing antibodies prevent the spread of pathogens, while efficient cellular immunotherapy is used to overcome T-cell exhaustion and unresponsiveness toward self-antigens. In such settings, the type I interferon (IFN) system mediates pleiotropic effects of the immune system that can be either immunostimulating or immunosuppressing. In a recent work, De Giovanni et al. identified a novel regulatory checkpoint by which type I IFN regulates CD4 + T-cell polarization. This study dissects the time point of type I IFN induction as a central regulator of the adaptive immune response that determines the balance between humoral and cellular immunity. These findings identify an intriguing and previously undescribed checkpoint that can potentially be manipulated for immunotherapy. Furthermore, the authors demonstrate that CD4 + T-cell polarization could be influenced by manipulating the IFN response during infection.When pathogens are detected by cells of the innate immune system, such as macrophages and dendritic cells (DCs), the expression of type I IFNs is induced. In infected and neighboring cells, type I IFNs cause the expression of IFN-stimulated genes (ISGs) that have antiviral properties and can inhibit the spread of infectious agents. Cells of the innate immune system respond to type I IFNs by enhancing antigen presentation and the production of cytokines and chemokines. Furthermore, parts of the adaptive immune system, such as antibody production by B cells and the effector function of T cells, are also affected by type I IFNs. 1 Viral infection mostly leads to the generation of type 1 helper T cells (T H 1) and follicular helper T cells (T FH ), which are subtypes of CD4 + T cells and have an impact on adaptive immunity. 2,3 The mechanisms by which pathogens lead to generation of various effector cells are incompletely understood. De Giovanni et al. analyzed the impact of two different virus infections on the polarization of CD4 + T cells. They used vesicular stomatitis virus (VSV), a cytopathic virus that induces potent neutralizing antibodies, and lymphocytic choriomeningitis virus (LCMV), a noncytopathic virus that elicits a robust cellular response. 4 Antigen-specific Tg7 or SMARTA CD4 + T cells were adoptively transferred prior to the infection of mice with VSV or LCMV, respectively. In VSV-infected mice, >40% of antigen-specific CD4 + T cells differentiated into T FH cells, whereas upon LCMV infection, CD4 + T cells differentiated into mostly T H 1 cells. Although the binding affinity of a T-cell receptor to an antigen influences T-cell fate, the authors showed that this effect on CD4 + T-cell polarization was independent of antigen affinity.Microscopy recordings showed that the infection influenced the dynamic behavior of antigen-specific CD4 + T cells. After VSV infection, antigen-specific CD4 + T cells were found primarily in Bcell follicles, while most antigen-specific T cel...

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Spatiotemporal regulation of type I interferon expression determines the antiviral polarization of CD4+ T cells

Cited by 73 publications

References 62 publications

Safe and effective two-in-one replicon-and-VLP minispike vaccine for COVID-19

Safe and effective two-in-one replicon-and-VLP minispike vaccine for COVID-19

Transcription tipping points for T follicular helper cell and T-helper 1 cell fate commitment

Add on the next level—the time point of the type I IFN response orchestrates the immune response

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