New approaches to study T cell activation, differentiation and plasticity in humans
Surface markers have been widely used to define subsets of effector and memory T cells. The surface expression of different combinations of chemokine receptors (CXCR3, CCR4 and CCR6) has allowed us to identify and isolate subsets of human memory Th1, Th2 and Th17 cells and to discover new subsets of IFN-gamma producing T cells and IL-22-producing T cells. It is however evident that heterogeneity of memory T cells is higher and there is a need to develop approaches for the identification of phenotypically and functionally distinct subsets that are relevant in the context of the immune response to different classes of pathogens or in different pathological conditions. The overall goal of this project is to define the molecular basis of human CD4+ T cell heterogeneity, which represents a fundamental aspect of the immune response. In particular we aim at identifying the mechanisms that determine T cell fate diversity in response to different classes of pathogens, the lineage relationship between different fates, and the degree of plasticity at distinct stages of differentiation. To achieve this goal, we propose to complement our well-established cell culture-based analytic approaches with new powerful methods to probe the whole functional heterogeneity of human T cells at the level of epigenome, transcriptome and proteome. We will also use recently developed gene editing methods to dissect pathways of naive T cell activation and differentiation, to resolve the level of plasticity and commitment of memory T cells, and to define the role of signal strength in T cell activation, differentiation, and function. We expect that these studies will significantly expand our basic understanding of T cell biology by unraveling further degrees of heterogeneity in human effector and memory T cells responding to different classes of pathogens, which is relevant for vaccine design. We will also gain knowledge on fundamental aspects of T cell activation and differentiation in humans and define ways how to manipulate the process for therapeutic applications.