Type III interferon exerts thymic stromal lymphopoietin in mediating adaptive antiviral immune response

Abstract

Previously, it was believed that type III interferon (IFN-III) has functions similar to those of type I interferon (IFN-I). However, recently, emerging findings have increasingly indicated the non-redundant role of IFN-III in innate antiviral immune responses. Still, the regulatory activity of IFN-III in adaptive immune response has not been clearly reported yet due to the low expression of IFN-III receptors on most immune cells. In the present study, we reviewed the adjuvant, antiviral, antitumor, and disease-moderating activities of IFN-III in adaptive immunity; moreover, we further elucidated the mechanisms of IFN-III in mediating the adaptive antiviral immune response in a thymic stromal lymphopoietin (TSLP)-dependent manner, a pleiotropic cytokine involved in mucosal adaptive immunity. Research has shown that IFN-III can enhance the antiviral immunogenic response in mouse species by activating germinal center B (GC B) cell responses after stimulating TSLP production by microfold (M) cells, while in human species, TSLP exerts OX40L for regulating GC B cell immune responses, which may also depend on IFN-III. In conclusion, our review highlights the unique role of the IFN-III/TSLP axis in mediating host adaptive immunity, which is mechanically different from IFN-I. Therefore, the IFN-III/TSLP axis may provide novel insights for clinical immunotherapy.

Keywords: IFN-III/TSLP axis; adaptive antiviral activity; adaptive immunity; thymic stromal lymphopoietin; type III interferon.

Figure 1

The IFN-III/TSLP axis in adaptive immunity. IFN-III and TSLP are both produce by epithelial cells, but perform different biological activities. IFN-III is critical in modulating tumor invasion or hypersensitivity disorders (such as autoimmune disease and asthma); TSLP is the pathogen of asthma and autoimmune disease but contradicts in cancer. Interestingly, both IFN-III and TSLP show direct or indirect antiviral activities on mucosal sites. The interaction between IFN-III and TSLP has also been revealed by the latest researches (33, 35). Therefore, the IFN-III/TSLP axis is responsible for adaptive antiviral immunity but is unclear in the context of cancer or hypersensitivity disorder.

Figure 2

Engagement of the IFN-III/TSLP axis in adaptive antiviral activity: environment decided. The IFN-III/TSLP axis exerts distinct adaptive antiviral activities in mice and human. In the murine environment (left), IFN-III induces TSLP production by virus-infected M cells and promotes the migration of CD103⁺ DCs, thereby promoting TSLP-dependent GC B cell response by Tfh cells and fostering high-affinity antibody production. Antigen-stimulated TSLP also regulates mucosal homeostasis by activating Tregs through the mTORC1 pathway. In the human environment (right), on the one hand, IFN-III can either inhibit antibody production or enhance GC B cell response by naïve B cells through the mTORC1 pathway; on the other hand, TSLP-activated DCs are capable of inducing naïve CD4⁺ T cells to differentiate into Th2 via the OX40L pathway, and this process may also depend on IFN-III.

Figure 3

Mechanisms of IFN-I in adaptive immunity: TSLP-independent. Epithelial cells-derived TSLP exerts adaptive antiviral activity by activating DCs that trigger CD8⁺ T cell amplification, B cell differentiation, and antigen-specific antibody secretion. IFN-I regulates adaptive immune response directly by stimulating immune cells (such as T cells or B cells), which is independent of TSLP, or indirectly by stimulating DCs to induce CD4⁺ T cells to differentiate into Tfh or Th1 cells that can activate antibody production by GC B cells.