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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