T-cell biology, Thymus and T-cell development, T-cell Tolerance and Immunity.
Major laboratory interests focus on the mechanisms that regulate the generation of a self-tolerant T-cell pool. These events occur within the thymus, an organ that provides specialised microenvironments to support the development of mature T-cells from their bone marrow derived precursors. In particular, epithelial cells within the thymus provide essential signals to these migrant precursors that regulate their proliferation, commitment, and differentiation. Defects in thymic epithelial cell development and function are known to be linked to autoimmunity and immunodeficiency, making analysis of these cells important in understanding normal immune system development and function. Specifically, we study:
Thymic Epithelial Cell Development And Function
Thymic epithelial cells provide unique environments to support the generation of a self-tolerance T-cell repertoire. Over several years we have focused on the cellular and molecular regulation of thymic epithelial cell development. Major findings include:
Identification of a bipotent progenitor for cortical and medullary thymic epithelium (Nature, 2006).
First demonstration of a role for the TNF-Receptor RANK in development of Aire-expressing medullary epithelial cells and the establishment of self-tolerance (J. Exp. Med. 2007).
Demonstrating the importance of thymic epithelial niches for optimal thymus growth and T-cell output (Blood 2007, J. Immunol. 2008).
T-cell Commitment, Development and Selection
As the thymus has no inherent haemopoeitic stem cell capacity, progenitors must be recruited to the thymus throughout life. We have investigated the mechanisms of thymus colonization and intrathymic T-cell development, and major findings are summarised below:
Thymus colonisation involves multiple T-cell progenitor subsets that home to the thymus differ in their responses to chemokines (Eur. J. Immunol. 2007)
Demonstration of a role for CCR9 during intrathymic T-cell development (J. Leuk. Biol. 2007).
Identification, of a clonal molecular signature of thymus settling progenitors (J.Immunol. 2011)
Lymphoid Tissue Inducer Cells At The Interface Between Tolerance and Immunity.
With Peter Lane’s laboratory, our research has highlighted a key role for Lymphoid Tissue Inducer (LTI) cells in the establishment of intrathymic medullary microenvironments that regulate central tolerance. Critically, we have also shown that LTI play an essential role in the generation of memory CD4+ T-cells, and we are currently investigating further the role of LTI and tolerance and immunity. Major findings include:
First demonstration of a role for RANKL+ LTI cells in the generation of Aire-expressing medullary epithelial cells (J. Exp. Med. 2007).
Identification of OX40L+ LTI as key regulators of memory CD4+ cells in the gut (J. Immunol. 2009).
Experimental Manipulation of Lymphoid Organs In Vivo
Using techniques based on in vitro manipulation of the thymus in combination with in vivo thymus transplantation assays, we recently defined precursor-product relationships in the developmental pathway of thymic epithelial cells (Nature 2006, J. Exp. Med. 2007). Within Birmingham, we collaborate with several laboratories including those of Peter Lane, Antal Rot, Chris Buckley and Jorge Caamano to study molecular and cellular regulation of T-cell migration and responses in both primary and secondary lymphoid tissues.