[Frontiers in Bioscience 16, 2461-2477, June 1, 2011]

Structure and function of the thymic microenvironment

Nancy Ruth Manley1, Ellen Rothman Richie2, Catherine Clare Blackburn3, Brian Gene Condie1, Julien Sage4

1Department of Genetics, Coverdell Center, 500 DW Brooks Drive, University of Georgia, Athens, GA, 30602, USA, 2Department of Carcinogenesis, University of Texas MD Anderson Cancer Center, Science Park Research Division, Smithville, TX 78957, USA, 3Medical Research Council Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JQ, United Kingdom, Departmnts of Pediatrics and Genetics, Stanford University, 269 Campus Drive, CCSR 1215 Stanford, CA 94305 USA

TABLE OF CONTENTS

1. Abstract
2. Introduction: Thymus structure and function through the lifespan
2.1.What is the thymic microenvironment?
2.2.Overview of thymus development and decline
2.3.Cellular components of the thymic microenvironment
2.4.Phenotypic hallmarks of the thymic microenvironment during involution
3. Formation of the microenvironment depends on crosstalk between TECs and multiple cell types
3.1.Thymocyte and TEC differentiation are interdependent
3.2.Epithelial-mesenchymal interactions and the role of NCCs in thymus development
3.3.Thymus compartment formation and elaboration of the vascular network
4. Evidence for thymic epithelial stem/progenitor cells in the fetal and postnatal thymus
4.1.Defining stem/progenitor cells
4.2.Evidence for fetal thymic epithelial stem/progenitor cells
4.3.Evidence for TESC/TEPC in the postnatal thymus
5. Regulation of the thymic microenvironment: proliferation, differentiation, or both?
5.1.Foxn1 is a key regulator of TEC differentiation and proliferation throughout the thymus lifespan
5.2.The role of cell cycle regulation in maintaining the size of the thymic microenvironment
6. Clinical and translational relevance of understanding the thymic microenvironment
7. Acknowledgements
8. References

1. ABSTRACT

Organs are more than the sum of their component parts - functional competence requires that these parts not only be present in the appropriate proportions, but also be arranged and function together in specific ways. The thymus is an excellent example of the connection between cellular organization and organ function. Unlike more familiar organs, such as lung or kidney, the thymus is not organized into easily identifiable structures such as tubes and ordered cell layers, but instead is a complex meshwork of microenvironments through which T cell progenitors migrate, receiving signals that instruct them to differentiate, proliferate, or die. Proper thymic organization is essential to the optimal production of a functional T cell repertoire. During aging, the thymus undergoes involution, largely due to degradation of the TEC microenvironmental compartment, which then fails to support optimal thymocyte development resulting in reduced output of naïve T cells. This review will summarize the current state of understanding of the composition and organization of thymic microenvironments and the mechanisms that promote their proper development and function.