Regulatory T cells in control of the immune response to acute bacterial infection and sepsis

点击翻译按钮获取中文摘要

The immune system is evolved to mount a rapid, protective response against infection. At the same time, it is tightly regulated in order that this response does not overshoot so as to cause inflammatory damage. A key way in which such regulation comes about is through the action of a white blood cell population termed regulatory T cells, or Tregs. Relatively little work has previously been done on the role that Tregs might play in regulating the immune response in the context of severe bacterial infection. These infections can involve sepsis, the condition whereby there is an inflammatory response throughout the body, often leading to organ failure or, in the condition termed septic shock , rapid fall in blood pressure. Septic shock leads to death in 40-70% of cases. There is thus an urgent need to gain a better understanding of the immunological events leading to this condition and so design better medicines. A current view suggests that it might be the consequence of an exaggerated, damaging, immune response. Little work has been done on the role of Tregs in controlling this, though we have recently been doing work to find out. The patient needs to mount a rapid and effective immune response to infection, so might this involve some mechanism for taking the brakes off with respect to Treg control, yielding a bigger response? Alternatively, perhaps bacteria have evolved mechanisms to subvert the immune response, producing substances that are able to further enhance Treg function and constrain immunity. A third possibility is that a large amount of control by Tregs is indeed brought to bear, but this is an appropriate response to limit disease damage. We will address these possibilities in a well-defined transgenic mouse model of gram-positive sepsis. The work involves defining the Treg changes that occur at the site of infection and in the whole body after infecting with the gram-positive bacteria, Streptococcus pyogenes. We will then see what happens if the influence of Tregs is removed, either by giving an antibody or by doing the work in knockout mice. These studies should aid our fundamental understanding of Tregs during bacterial infection, as well as offering clues for future therapeutic manipulation of the immune response in septic shock.