Investigating how memory T cells regulate immune responses to re-infection and cancer

Immune responses to pathogens are essential for human health. After seeing pathogens for the first time, our immune system can remember this encounter and respond to re-infection with the same pathogen more effectively. This process, termed ‘immunological memory’, is vital in allowing us to deal with repeat infections, and is also the cornerstone of successful vaccination. Key cells in promoting memory responses in the immune system are T-cells. These cells are activated during initial infection, with most dying off when the infection is cleared, but some becoming long-lived memory T-cells that respond more quickly and effectively to re-infection. Understanding how memory T-cells function is therefore crucial in understanding how we successfully fight infection, and in the design of vaccines to promote immunological memory. Our exciting new data has identified an unexpected role for a subset of memory T-cells in regulating responses to re-infection. Thus, a proportion of T-cells previously classified as CD4+ effector/memory T-cells have the ability to activate the cytokine TGF-beta and play an unexpected role in keeping the brakes on the T-cell response during viral re-infection in the lung. In the absence of this pathway, more damage occurs in the lung during re-infection. Thus, we have uncovered a pathway that appears to limit the immune system during re-infection to prevent unwanted inflammation and tissue injury. It is now critical that we determine in detail the properties and characteristics of these cells, why they are specialised to suppress tissue damage during re-infection, and whether they function during specifically during viral re-infection in the lung or to other immune challenges as well. Additionally, we have discovered that these suppressive memory T cells are present in tumours, where they may play roles in suppressing anti-tumour immune responses. The overarching aim of this project is to investigate how a newly identified sub-population of CD4+ T-cells regulate immune responses to lung re-infection and determine the broader importance of this pathway in other tissues, and cancer. This will be achieved via the following three aims: Aim 1: Investigate the molecular, functional, and spatial characteristics of suppressive CD4+ effector/memory T-cells that limit immunity during lung re-infection. Aim 2: Determine the broader role of suppressive CD4+ effector/memory T-cells in inflammatory challenge. Aim 3: Examine the role of suppressive CD4+ effector/memory T-cells in regulation of cancer immunity. The enhanced understanding generated will provide fundamental insights into how immunological memory is regulated to help us balance responding robustly to pathogens upon re-infection without causing tissue damage. Our work will also determine other situations where these pathways act and could be targeted in disease or exploited therapeutically – for example targeting these cells to enhance immune responses in cancer.