New Switch Of The Immune System Discovered
At the Institut Curie, Inserm researchers, in collaboration with collegues from Dynavax(1), have discovered a new mechanism controlling the choice in humans between two lines of defense in the event of attack. In the presence of viruses or bacteria, the immune system can trigger a response that is rapid but devoid of memory – innate immunity – or a response that takes longer to put in place but is more specifically targeted – adaptive immunity.
The essential prerequisite to the proper functioning of innate immunity is the “turning on” of the protein PI3-kinase. Once PI3-kinase is activated, the immune response is triggered, leading to the production of type I interferons, the spearhead of innate immunity, which destroy the body’s invaders. This discovery opens up new therapeutic prospects since it may suggest ways of restoring the function of innate immunity, which is overactivated in autoimmune diseases and inhibited in certain cancers.
The body is often faced with attacks from outside (viral or bacterial infection) and sometimes from inside, because of the dysfunction of its own cells (cancer), and defends itself by activating its immune system. There are two types of defence. The first is innate immunity: this has no memory, and is permanently on guard to detect and destroy abnormal cells, tumor cells, or virus-infected cells. The second, which takes longer to initiate, is adaptive immunity, which specifically targets an invader. This response requires a education phase during which the cells of the immune system learn to recognize their enemy.
Dendritic cells, the body’s “sentinels”, are the first line of defence against invading pathogens: they recognize viruses and bacteria and then trigger an immune response, which, depending on the case, may be innate or adaptive. In response to an intruder, the so-called plasmacytoid dendritic cells can either produce large amounts of interferons, molecules that trigger a rapid response against viral infections, or “specialize” and become cells able to teach the immune system to recognize the pathogens.
At the Institut Curie, Vassili Soumelis(2) and his team (“Immunity and Cancer”, Inserm/Institut Curie Unit 653) have discovered how the dendritic cells choose between the two types of immune response. First, whatever the response, the presence of an intruder stimulates the TLR receptor inside the dendritic cells. Only then is the choice made between the two types of response. The PI3-kinase signaling pathway is activated, and the innate response is triggered. Kinase PI3 is the switch that turns on a whole cascade of proteins inside the cell. Information on the presence of an intruder in the body is thus transmitted to its final destination, in the cell’s nucleus, where the protein IRF-7 (transcription factor) modifies the expression of specific genes and so alters the cell’s behavior. In this specific case, IRF-7 induces the production of type 1 interferons (interferon-alpha, for example), which will bring about the destruction of the viruses and strongly activate various cells of the immune system.
Vassili Soumelis MD, PhD at the Institut Curie explains: “Activation of the protein PI3-kinase is one of the very first steps needed for the production of large quantities of type 1 interferons, leading to the triggering or strengthening of the innate immune response.”
In certain autoimmune diseases this innate response overstimulated, leading to an abnormal defense reaction of the immune system, which attacks its own cells, tissues, or organs. In some cancers, on the other hand, the innate response is virtually absent. It may be that the cancer cells are able to block the PI3-kinase signaling pathway. Through this discovery, Vassili Soumelis and his collaborators hope, in time, to develop new treatments for use in autoimmune diseases and oncology. By acting on PI3-kinase, it may be possible to adapt the innate response, so as to inhibit it in the treatment of autoimmune diseases and boost it in cancer treatment.
Dynavax Technologies Corporation, Berkeley, CA 94710, USA.
Plasmacytoid predendritic cells (pDCs) are the main producers of type I interferon (IFN) in response to Toll-like receptor (TLR) stimulation. Phosphatidylinositol-3 kinase (PI3K) has been shown to be activated by TLR triggering in multiple cell types; however, its role in pDC function is not known. We show that PI3K is activated by TLR stimulation in primary human pDCs and demonstrate, using specific inhibitors, that PI3K is required for type I IFN production by pDCs, both at the transcriptional and protein levels. Importantly, PI3K was not involved in other proinflammatory responses of pDCs, including tumor necrosis factor alpha and interleukin 6 production and DC differentiation. pDCs preferentially expressed the PI3K delta subunit, which was specifically involved in the control of type I IFN production. Although uptake and endosomal trafficking of TLR ligands were not affected in the presence of PI3K inhibitors, there was a dramatic defect in the nuclear translocation of IFN regulatory factor (IRF) 7, whereas nuclear factor kappaB activation was preserved. Thus, PI3K selectively controls type I IFN production by regulating IRF-7 nuclear translocation in human pDCs and could serve as a novel target to inhibit pathogenic type I IFN in autoimmune diseases.