Understanding basic mechanisms of CD4 immunity and its regulation in relation to autoimmunity and cancer pathogenesis

T cells make up a significant proportion of the white blood cells that, as part of our immune system, defend our body against attack by pathogens. A subpopulation of T cells, CD4 or helper T cells, when stimulated by exposure to infection, provides help to other protective cells, such as antibody producing cells, to defend us against disease. Once activated, some CD4 T cells go on to develop long-term protective capabilities, which we call immune memory, and which allows us to deal with repeat infections immediately and often without being aware of the infection. These actions of CD4 T cells are the basis of the vaccination programmes used to protect children and societies everywhere from disease epidemics. Although vital to our health and often survival by conferring immunity on us, CD4 T cell responses can be highly damaging when they are involved in attack on our own tissues, that is when they become autoimmunity. Autoimmune conditions - just two examples are type 1 diabetes and many forms of arthritis - affect the lives of many people, use valuable resources in our Health Services, and are very difficult to treat. Damaging CD4 T cell responses can be suppressed, but current immuno-suppression is not specific, so there is often a cost in the form of secondary infection due to adverse side effects on new T cells preparing to fight new infections, and on other cells and tissues of the immune system. We would like to be able to suppress unwanted immune responses while conserving protective ones, and with that in mind have been investigating how T cells interact with one another and with other players in the development of immunity through receptors at their cell surfaces. By knocking out the genes that encode two particular cell surface receptors, called CD30 and OX40, we have found them, and the cell they occur on, to be essential for CD4 memory - without them, vaccination does not work. We believe this to be a crucial discovery, because we now know which cell type to preserve if we want to keep protective immune memory, and can begin to form a strategy to inhibit damaging autoimmunity at the same time. Besides supporting CD4 memory T cells, this cell type, called an LTi, may also be important in helping another type of CD4 T cell, a regulatory T cell. Regulatory T cells (Tregs) are the immune system's normal counterbalance, that is they keep a check on the rate of growth of helper T cells as they fight infection, and are usually responsible for heading off autoimmunity. Therefore it is important to understand how Tregs are made and how they are kept alive. Although Tregs are important for suppressing autoimmunity, they have also been implicated in suppressing protective anti-tumour immune responses, and indeed suppressing regulatory T cell function has been linked with the improved anti-tumour immunity. However, because Tregs also suppress autoimmune responses, CD4 driven autoimmunity is a major side effect. Our data shows, however, that you can suppress CD4 driven autoimmunity while suppressing Treg function. We think this might be an effective strategy to promote anti-tumour immunity in cancer patients without the side effects of autoimmunity, and could therefore have wide implications. The research we are proposing is to discover the details of interactions between CD4 T cells, LTi and Tregs and the way these interactions use specific cell surface receptors and affect other parts of the immune system. We expect to be able to use these details to design improved therapies for the many health problems arising from mis-directed immunity.