Novel mechanisms of regulatory T cell mediated suppression: a fundamental role for VPS34

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The immune system provides us with life-long protection against infectious agents. Specialised cells called T cells can both orchestrate the activities of other immune cells and kill infected cells directly. Remarkably, a small subset of T cells, called regulatory T cells (Tregs) are required to keep all the other T cells (conventional T cells, or Tcon) in check. Although Tregs comprise only about 1% of all the white blood cells, we cannot survive without them. Hence, children that lack a functional version of a gene called FOXP3 which is essential for Tregs do not live beyond two years, at which point their developing immune system turns against them, leading to a lethal syndrome known as IPEX. Mice that lack functional FOXP3 also die between 6 weeks because of an unrestrained immune attack against their organs and microorganisms in their skin and gut.What remains a puzzle is how such a small immune cell population can have such enormous importance for maintaining health. How do Tregs control the activity of the much more abundant Tcon? We have discovered that an enzyme called VPS34, originally identified in yeast, is essential for the function of Tregs. This is an important distinction from Foxp3, which is required for the development of Tregs. Therefore, FOXP3-deficient mice lack completely Tregs, whereas if we deleted the gene encoding VPS34, and that only in Tregs, we find normal numbers of Tregs in immune-related organs, but the mice nonetheless do not survive beyond 4-6 weeks. Normally, mice can live for 2-3 years. We therefore hypothesise that by gaining a better understanding of what VPS34 does in Tregs, we can also learn more about how Tregs work and answer the question about which function is absolutely essential for their ability to restrain Tcon.We will use several different experimental approaches to address this question. Most of the work will take advantage of a genetically modified mouse model in which the gene for VPS34 is deleted only in Tregs. Once mechanism through which Tregs are thought to work is by consuming certain stimulatory protein molecules so that they become unavailable for Tcon. We have already established that VPS34-deficient Tregs are still able to bind these proteins and internalise them. We will now follow what happens to these proteins once they have been transported inside the Tregs. Normally, they would be digested and degraded, but we suspect that this process is disrupted in Tregs lacking VPS34.We will also use mice in which only about half the Tregs lack VPS34. Such mice live a normal life span. We will challenge such mice by either implanting tumour cells under the skin or by infecting them with bacteria. This will stimulate both Tcon and Tregs to multiply and change from a resting state to a highly activated state. We can then compare Treg with or without VPS34 in the same mouse and ask: does whether lack of VPS34 interfere with the ability of Tregs to be activated and perhaps reach their full immune suppressive potential. Each T cell has about 6000-8000 different kinds of proteins. We have been able to measure these proteins in normal and VPS34-deficient Tregs. We can therefore determine whether without VPS34, you end up with more of some proteins, and less of others. Many of the proteins that are altered in absence of VPS34 are involved in cellular metabolism (i.e. processes that regulate how Tregs take up and use nutrients). We will determine if some of these metabolic activities affect Treg function and suppression. We believe that these complementary approaches will lead us to discover novel aspects of Treg function that might one day can be exploited for therapeutic purposes, for instance by designing drugs that either enhance or inhibit Treg function, and that could be used in the context of cancer or autoimmune diseases.