IFNAR1 signaling in NK cells promotes persistent virus infection

Abstract

Inhibition of type 1 interferon (IFN-I) signaling promotes the control of persistent virus infection, but the underlying mechanisms remain poorly understood. Here, we report that genetic ablation of Ifnar1 specifically in natural killer (NK) cells led to elevated numbers of T follicular helper cells, germinal center B cells, and plasma cells and improved antiviral T cell function, resulting in hastened virus clearance that was comparable to IFNAR1 neutralizing antibody treatment. Antigen-specific B cells and antiviral antibodies were essential for the accelerated control of LCMV Cl13 infection following IFNAR1 blockade. IFNAR1 signaling in NK cells promoted NK cell function and general killing of antigen-specific CD4 and CD8 T cells. Therefore, inhibition of IFN-I signaling in NK cells enhances CD4 and CD8 T cell responses, promotes humoral immune responses, and thereby facilitates the control of persistent virus infection.

B cell–derived IL-27 promotes control of persistent LCMV infection

“…In addition to regulating survival and functions of virus-specific CD4 T cells, IL-27 has been shown to play an important role in supporting Tfh functions during ovalbumin priming ( 28 ). Recent findings also indicated that Tfh cells are essential for the generation of LCMV-specific antibodies that drive clearance of persistent LCMV infection ( 7 , 16 ). Therefore, we investigated the impact of B cell–derived IL-27 on the numbers and function of Tfh cells during the chronic phase of LCMV infection.…”

“…Our group recently showed that blockade of IFN-I signaling led to increased numbers of Tfh cells in both WT and IL-27ra KO mice during persistent LCMV infection ( 6 – 8 , 31 ), and thus we further tested whether anti-IFNAR1 immunotherapy is able to improve functions of CD4 T cells and promote viral clearance. We first assessed Tfh numbers and function following anti-IFNAR1 antibody treatment at day 40 p.i.…”

“…Seven- to 12-wk-old mice were injected intravenously with 2 × 10 6 focus-forming units (FFUs) of LCMV Cl-13. Viral titers were assessed by focus assays using Vero cell monolayers as previously described ( 7 , 42 ). All experiments were conducted in accordance with guidelines and approval of the Institutional Animal Care and Use Committee of The Scripps Research Institute.…”

“…Initially upon infection, LCMV Cl-13 induces higher production of type 1 interferon (IFN-I) and expression of immunoregulatory molecules such as interleukin-10 (IL-10) and programmed cell death ligand 1 (PD-L1), which restrains T cell functions and sets up virus persistence. Blockade of IFN-I, PD-1/PD-L1, and IL-10 were shown to improve functions of virus-specific T cells to kill infected cells and produce effector cytokines such as IFN-γ, tumor necrosis factor-α (TNF-α), and IL-2 ( 6 – 12 ). During the later stages of persistent LCMV infection, virus-specific CD4 T cells display differentiation bias toward T follicular helper (Tfh) cells and produce the immune stimulatory cytokine IL-21 to provide help to both CD8 T cells and B cells.…”

Natural killer cell immunosuppressive function requires CXCR3-dependent redistribution within lymphoid tissues

“…Of note, transient blockade of IFN-I early during LCMV infection can enhance antiviral T-and B-cell responses (30). Ablation of the IFNAR on NK cells exerts a similar effect (31). In MCMV and SIV/HIV infections, where NK cells exhibit potent antiviral function, this migration of NK cells to T-cell zones serves to protect these tissues from virus (15,19).…”