Regulation of T cell differentiation by stimulation strength

The immune system defends the body against infections. It is made up of a collection of specialised cells that fight infection in different ways. CD8 T cells are a type of immune cell that can find and kill virus-infected cells. When a T cell first encounters a harmful invader, it is stimulated to multiply, and its "daughter" cells specialise further to perform different functions. Some cells fight the current infection, while others become "memory" cells that provide defence against the same infection in the future. Previous research has shown that the strength of T cell stimulation in this initial encounter affects how the daughter T cells specialise. Many questions remain about how this occurs. In this proposal, I will answer these questions by investigating how T cells make decisions about the type of specialised responses they will develop. To do this, I will compare T cells after strong versus weak virus stimulation and use state-of-the-art techniques to examine which genes are turned on and off within individual cells. I will also examine how movement within lymph nodes and interactions with other types of immune cells impact this process. Finally, I will compare daughter cells that developed after strong stimulation versus those that developed after weak stimulation and test how well they fight a repeat infection. These data will reveal how T cells control their responses to provide the right balance of protection against current and future threats.

This work will improve understanding of a fundamental process of the immune system and is also relevant for the design of therapies that aim to manipulate T cell responses. For example, long-lasting T cell memory is an important target of vaccination, and understanding how these responses develop may benefit vaccine design strategies. As the project will reveal fundamental properties of immune cell activity, it may also influence work in other fields of immunology including cancer immunotherapy and autoimmune disease research.

Through the process of differentiation, a single naïve T cell can contribute to a wide variety of effector and memory responses, providing protection against both current and future pathogenic threats. Understanding the mechanisms by which differentiation fate decisions are made is important for rational design of therapeutics that aim to elicit specific types of T cell responses, such as vaccination and cancer immunotherapy. The affinity with which a naïve T cell binds an antigenic ligand controls the strength of stimulation the T cell experiences and can skew the distribution of resulting differentiated cells among effector and memory subsets. This proposal seeks to uncover the mechanisms underlying the effects of stimulation strength on CD8+ T cell differentiation and determine its impact on the protective functions of differentiated T cells. I will use cutting-edge single-cell genomic and multi-omic techniques coupled with in vivo influenza infection models to interrogate the impacts of altering stimulation strength on CD8+ T cell effector and memory responses. Specifically, this proposal will investigate 1) the transcriptomic and epigenetic underpinnings of altered differentiation outcomes, 2) the relative contributions of stimulation strength and localisation within the lymph node in determining differentiation fate, and 3) the functional capacities of cells that have achieved the same differentiation fate via initial stimuli of different strengths. Together these data will shed light on the mechanisms by which CD8+ T cells, armed with a single set of intracellular machinery, can tune their differentiation according to stimulation context. This will be valuable information for understanding the host response to viral infection, which remains one of the major threats to human health.