“An understanding of the mechanisms of the immune system is critical in order to design better vaccines and better methods to prevent the spread of a virus and is a key element in the treatment of viral diseases.”

It has been questioned for many years exactly which member of the transcription factor family, termed Interferon Regulatory Factors (IRFs), is actually essential to the induction of interferon (IFN) production, the event essential to anti-viral immune response. There are two major pathways that activate the IFN genes, namely, the cytosolic pathway and Toll-like receptor (TLR) pathway that utilizes the adaptor molecule, MyD88, for signaling. In fact, TLR signaling pathway is the focus of much attention in immunology, playing a central role in linking the innate and adaptive immune responses, and it has been known that a subset of dendritic cells, termed plasmacytoid dendritic cells (pDCs) is activated by TLR9 or TLR7 to induce a very high level of IFNs upon stimulation by their cognate ligands.

In this paper, it was demonstrated for the first time that IRF-7 is the master regulator of IFN response for both cytosolic and TLR pathways. All elements of the IFN response, whether the systemic production of IFN for innate immunity by cytosolic pathway or the local action of IFN from pDCs by TLR9 stimulation for adaptive immunity, are subject to the control of IRF-7. This work therefore resolved one of the long-sought issues of the regulation of the IFN-dependent immune response.

The paper showed that IRF-7 is essential for the systemic induction of type-I IFNs in innate antiviral immunity (through the MyD88-independent pathway) and for the local induction of type-I IFNs by pDCs that influence CD8+ T-cell adaptive immunity (through the TLR-activated MyD88-dependent pathway). The paper describes a new discovery pointing to the importance of IRF-7 in inducing all type-I IFN responses, and shows that it might be possible to manipulate IFN responses in clinical situations using compounds that target specific cellular compartments or that alter cellular trafficking.

Interferon is one of the most critical molecules produced in our body to defend against invading pathogens, such as viruses. However, it can also be harmful to the body if produced constitutively, therefore, the interferon gene is usually "switched off" in normally growing cells. When cells get infected by viruses or other pathogens, the gene is switched on to produce this important molecule in order to defend the body. This switching mechanism remained elusive for a long time, and this paper now demonstrates that the gene transcription factor, called IRF-7, governs the switching of the interferon gene.

My research career on cytokines began from the characterization of the human fibroblast IFN gene (now referred to as IFN-b) in 1979. In collaboration with Dr. Charles Weissmann and colleagues, we elucidated the primary structure of two IFN proteins (IFN-a and -b) and demonstrated that IFN-a and IFN-b genes constitute a gene family; this turned out to be the first of the numerous cytokine gene families to be identified. We also identified and characterized a human interleukin gene—the IL-2 gene—and generated recombinant IL-2, thereby making possible the study of the molecular basis of lymphocyte proliferation. Availability of these recombinant cytokines has made their use for clinical applications in cancer, hepatitis, and multiple sclerosis, and also for studies of molecular signaling mechanisms possible.

An understanding of the mechanisms of the immune system is critical in order to design better vaccines and better methods to prevent the spread of a virus and is a key element in the treatment of viral diseases.