Title: Cortical Thymic Epithelium: Defining Developmental Pathways and Specialization for Positive Selection
Funder: Medical Research Council

Abstract: The thymus provides the primary site for T-cell development within the body, T-cells being key immune cell types pivotal to the orchestration of immune responses to invading pathogens. Within the thymus, specialized thymic epithelial cells provide essential microenvironments supporting T-cell development, ensuring that functional pathogen-reactive T-cells survive, whilst non-functional and auto-reactive T cells are deleted. Thymic epithelial (TE) microenvironments can be phenotypically and functionally split into two main specialized compartments being cortex and medulla, each facilitating specific T-cell developmental stages. Cortical thymic epithelial cells (cTEC) provide signals enforcing T-cell lineage restriction on thymus colonizing haematopoieitic precursors and also essential soluble factors providing survival and directional migration signals. In addition, cTEC play a unique and highly specific role in the processing and presentation of a unique array of self-peptides that are presented at the cell surface in association with MHC class-I and ?II molecules. The significance of such self-peptide presentation by cTEC is due to the random nature with which T-cells generate their T-cell receptors (TCR), being molecules expressed at the T-cell surface potentially capable of detecting both self and foreign-antigen and inducing T-cell activation. Importantly, cTEC presented self-peptide:MHC complexes positively select functional T-cells whilst screening-out T-cells bearing non-functional TCR. In addition, it has also been demonstrated that cTEC possess an exclusive capacity to process and present a highly unique array of self-peptides responsible for generating a highly diverse array of T-cells capable of responding to a similarly diverse range of antigen. Positively selected T-cells subsequently migrate to medullary regions where T-cells are screened for auto-reactive specificity, with self-reactive T-cells undergoing deletion before na?ve T-cells are exported to the periphery. Whilst the development and functioning of medullary TE has been a recent focus of research activity providing important data on the biology of such cells, cTEC developmental and functional-mechanisms remain uncertain. It is the purpose of this study to investigate how thymic epithelial microenvironments are established and maintained through the functional identification of cTEC-precursors and define the mechanisms regulating their expansion resulting in the formation of mature cortical microenvironments. In addition, this study will also investigate cTEC heterogeneity in terms of functional capacity to mediate positive selection, and define mechanisms involved in imparting cTEC with the functional ability to positively select a diverse array of T-cells. Such data will not only increase our basic understanding of events regulating T-cell development but may also provide information complementary to the development of strategies targeted towards manipulation of thymic epithelial development and function leading to improved T-cell generation and ultimately enhanced immuno-protection efficiency.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM