Investigating the molecular basis of heterogeneity and survival in memory CD4 T cells

Our immune systems recognise and respond to the pathogens that infect us and cause disease. An important element of our immune system is its ability to learn from previous infections and provide better protection should we meet the same pathogen again. We achieve this by forming immune memory cells that act quickly in response to subsequent infections. This ability to remember past infections is the basis for the success of vaccines. Most vaccines work be training immune cells called B cells to make antibodies that stick to the pathogen and stop it infecting us. Some pathogens, including the viruses that cause COVID19 and the flu, can change how they look and stop the antibodies sticking to them. This allows the virus to sneak back into our bodies. Fortunately, we have other immune cells that can remember past infections. These include CD4 T cells, known as the orchestrators of immune responses. CD4 T cells work with many other cells to control and clear pathogens. But we don't know enough about memory CD4 T cells to design vaccines that drive the generation of the most protective cells. We study the CD4 T cells that recognise flu viruses. We ask how memory CD4 T cells are made, how they change over time, and how they protect us against subsequent flu infections. To do this, we made a unique mouse that enables us to easily identify the CD4 T cells that recognise flu. Our first question is based on our finding that the memory CD4 T cells that form following a flu infection are very heterogenous. We want to ask when this heterogeneity develops, whether it is different depending on where the memory CD4 T cells are found in the body, and how it is affected by a subsequent infection. We will examine individual memory CD4 T cells to ask what molecules might control their generation and survival and how the cells maintain their identity. These data will help us understand the rules that affect the lifespan and function of these important cells. One way CD4 T cells control viruses is by communicating with other cells by making proteins called cytokines. Only some memory CD4 T cells can make cytokines. We found that the memory CD4 T cells that can make cytokines are able to stay alive for longer periods of time than those that can't. We will examine this enhanced survival more closely and ask whether these cells can keep making cytokines throughout their lifetime or whether they switch to being a different type of memory cell. For our last question, we will ask which molecules are important in the survival of a particular population of memory CD4 T cells. These are called multifunctional CD4 T cells and they can make several different types of cytokines. They have been linked to protection from various infections in animal models and in humans. We have chosen to examine the role of two molecules, Myc and Foxo1, based on our current studies. Multifunctional CD4 T cells make more of these molecules than other memory cells, suggesting that Myc and Foxo1 are important for how they survive and/or function. We will manipulate these molecules and ask whether and how this affects the memory CD4 T cells that form following flu infection. These experiments may help explain why multifunctional cells are more protective than other memory populations and potentially provide clues on how we could design vaccines to make better memory CD4 T cells. Together, our studies will provide us with a much broader and deeper understanding of memory CD4 T cells. We will reveal new knowledge about how these cells form, survive and function to protect us from infectious disease.