key: cord-0951768-ua3yp5an
authors: Wedekind, Angela; Fritzsch, David; Kröger, Andrea
title: Add on the next level—the time point of the type I IFN response orchestrates the immune response
date: 2020-04-28
journal: Cell Mol Immunol
DOI: 10.1038/s41423-020-0442-7
sha: 8818da327adbc80b1b54cd544ad865470f6d81cf
doc_id: 951768
cord_uid: ua3yp5an

nan

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 cells were outside these structures after LCMV infection. To investigate differences during CD4 + T-cell priming, the cellular and molecular composition of the "priming-niches" were analyzed by NICHE-seq. 5 This method combines the marking of areas in the lymph nodes (LNs) that contain antigen-specific CD4 + T-cell clusters by photoactivation and single-cell RNA sequencing to spatially reconstruct immune niches. The priming niches of VSV-and LCMV-infected mice differed in their cellular composition. After VSV infection, B cells and NKp46 + cells were overrepresented, and LCMV infection led to the accumulation of CD8 + T cells and CCR2 + inflammatory monocytes. By using different conditional knockout and transgenic mice, the researchers determined that the different cellular compositions of the priming niches did not initially influence CD4 + T-cell polarization. Instead, they identified the interaction between DCs and cognate CD4 + T cells as the main stimulus for the differentiation of both T FH and T h 1 cells. It is known that IL-6 promotes early T FH differentiation 6, 7 and that this effect depends on the induction of type I IFN. 8 Kinetic analysis of different IFNs and two representative ISGs isolated from the priming niches of the LNs after infection with VSV and LCMV was performed. The magnitude of type I IFN induction did not significantly differ between the two infections, but VSV induced an earlier wave of type I IFN, whereas LCMV induced a delayed and prolonged wave of type I IFN. To examine the impact of the general existence of a type I IFN response on CD4 + T-cell polarization, the type I IFN response was either blocked by specific anti-IFNAR-1 antibodies or induced by poly(I:C) treatment.

Whereas blocking the early IFN response during VSV infection inhibited T FH polarization, induction of the early type I IFN response during LCMV infection induced T FH polarization, indicating that the time point of IFN stimulation is an important regulator of CD4 + T-cell polarization. Together with previously described results, the authors determined the type I IFN-induced expression of IL-6 in DCs by assessing the composition and transcriptional state of DC subsets after early and late type I IFN sensing. They observed that the IL-6 expression of DCs drove T FH cell polarization in response to early (VSV) but not to late (LCMV) type I IFN signaling. This result indicates that spatiotemporal regulation of type I IFN expression determines whether DCs in the lymph node produce the cytokine IL-6 and shape antiviral CD4 + Tcell polarization (Fig. 1) .

The study conducted by De Giovanni et al. highlights the temporal component of IFN induction for the regulation of CD4 + T-cell polarization toward T FH or T H1 cells (Fig. 2) . These findings provide new information for understanding the outcome of viral infections and further advances in handling the manipulation of immune responses in the desired direction for vaccine development. However, further investigations are of utmost interest. It remains unclear how other cellular sources of IL-6 influence antiviral CD4 + T-cell polarization. In addition, the preceding relative contribution of all cells in the LN to type I IFN production was itself an unsolved question. Aside from the polarization of CD4 + T cells, the level of induction and the temporal occurrence of IFN have far-reaching consequences. In the case of virus infections, IFN not only limits the viral load but also has beneficial immunostimulatory functions. In the case of influenza infections, the high expression level of type I IFN also leads to the massive induction of proinflammatory cytokines such as TNF, IL-1β, IL-6, and chemokines, which are ultimately responsible for pathological effects in the lung. 9 A temporal effect of IFN-mediated pathology can also be observed during coronavirus infection. Here, only an early induction of type I IFN was beneficial and reduced viral replication, whereas a late induction of type I IFN was associated with dysregulation of inflammatory macrophages and immunopathology. 10 In summary, the work of De Giovanni et al. adds an important piece to an incomplete puzzle of IFN function and adds spatiotemporal regulation as a new dimension. By characterizing the cellular and molecular composition of the LN niches where CD4 + T-cell polarization occurs and identifying the causative cytokine dynamics, this work generated important knowledge with respect to antiviral responses and their possible pharmaceutical utilization.

Competing interests: The authors declare no competing interests. Fig. 1 Different expression of type I IFN and IL-6 leads to different antiviral T-cell responses. In lymph nodes, the early expression of type I IFN during a viral infection leads to a significant production of IL-6 and further to an effective T FH response. The delayed availability of type I IFN does not result in significant IL-6 production and is connected to a T h 1 response. If no type I IFN is available during a viral infection, no IL-6 is produced, but a T h 1 response is still established. In the lymph node, the early availability of type I IFN after a VSV infection leads mainly in type 2 conventional dendritic cells (cDC2s) and monocyte-derived dendritic cells (moDCs) to an increased production of IL-6. This effect drives naive T cells in the paracortical area to differentiate into T FH cells. They migrate into the follicular area and facilitate a strong humoral response by promoting the production of effective neutralizing antibodies. The delayed availability of type I IFN associated with LCMV infection does not influence DCs toward considerable IL-6 production. As a result, a large number of naive T cells differentiate into T h 1 cells and, in contrast to T FH cells, promote antiviral activity facilitated by a cellular response.

Add on the next level-the time point of the type I IFN response. . .

A Wedekind et al.

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