A novel pathway in the control of memory T cell function during immune responses to viral re-infection.

When we are infected with a microbe such as a virus for a second time, we deal with it faster and more efficiently than the first time. This occurs because of a phenomenon called immunological memory, and is the cornerstone of how vaccinations protect us. Crucial cells underpinning this better immune response are memory T cells. However, we do not understand how these cells are controlled to fight off infections quickly and effectively, but not cause harm to our own bodies in the process.

Our recent work has identified a new pathway by which memory T cell responses are controlled. Using mouse models, we have discovered that certain types of memory T cell can limit how strong the immune response is during viral re-infection, via a molecule called TGF-beta. Removing this pathway experimentally appears to promote a more rapid response to re-infection. This raises many important questions that we will address in this project: How is the novel pathway controlled? In what way does it contribute to the immune response to viral re-infection? Is this pathway active in humans when re-infected with a virus? Together, work in this proposal will characterise this new phenomenon, increase our understanding of how immunological memory works and identify new potential ways of promoting more effective responses to viral infection.

Immunological memory underpins how we respond to pathogens more robustly upon re-infection, and how vaccinations work. Memory T cells are critical to these responses. However, it is poorly understood how memory T cells are regulated to promote eradication of the pathogen upon re-infection, whilst preventing over-exuberant responses that could damage the host.

In new preliminary work we show that a subset of CD4+ effector memory T cells activate the cytokine TGF-beta, via the cell surface receptor integrin alphav beta8. Intriguingly this pathway appears to suppress the CD8+ T cell response during murine models of influenza re-infection and experimentally removing the pathway promoted a stronger response that increased viral clearance. This raises many important questions on how this contributes to the regulation of CD8+ T cells.

In this project we will characterise the cellular and molecular mechanisms underlying this new paradigm, identify its functional importance in host immune defence, and its role in regulating responses to viral re-infection in humans. The results will provide a step-change in our understanding of how memory T cell responses are controlled during viral infection, and reveal candidate mechanisms that could be targeted to promote more effective responses to infection.