Cellular and transcriptomic analysis of regulatory T cells in streptococcal infection

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This proposal is concerned with a population of white blood cells termed ?regulatory T cells? (Tregs). Their role in the body is to damp down other immune cells, preventing inflammatory ?overshoot?. We wish to examine what they do in a particular setting of bacterial infection: infections with Streptococcus pyogenes cause diverse conditions from sore throat to scarlet fever, rheumatic heart disease, sepsis and necrotising fasciitis (?flesh-eating disease?). We know that the interplay between the body and this bacterium is a complex one: on the one hand, a robust immune response is required to defend the body, while on the other, many of the disease manifestations are themselves a consequence of over-exuberant immunity. It is immediately apparent that there is likely to be an important role of Tregs. The Altmann lab has already shown (in mouse models) that there is a very rapid up-regulation of Tregs and molecules associated with them at the site of infection with this bacterium. The aim of this new proposal is to start building up an understanding of what happens in human cells. The proposal brings together investigators with highly complementary interests in this area in Singapore and London ? Altmann (Imperial) has been interested in models of streptococcal sepsis and the role of Tregs, Rotzschke (SiGN) has been involved in the detailed cellular and molecular analysis of Tregs, and Yang (SiGN) uses DNA microarray technology to describe immune responses. This latter approach is a very powerful one, allowing comparative analysis of cells that have been treated in different ways by looking at tens of thousands of human genes and asking, in a particular situation, which genes are turned up and which turned down. The 3 teams will build a close collaboration through annual workshops, monthly videoconferences, and by sending personnel between labs to work together. The central group of experiments depend on culturing cells from human tonsils, either in the presence or absence of Tregs, then infecting the cultures with various versions of Strep, of varying virulence. We will compare what happens, with or without Tregs, in terms of the presence of specific cell populations and gene by gene, though array anaysis. We will back up these human studies with experiments whereby we give the Strep to mice that either have normal Tregs, or have had them genetically knocked out. These experiments should lead to an improved understanding of the immunological events controlling these diseases.