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Blood, 1 December 2006, Vol. 108, No. 12, pp. 3777-3785.
Prepublished online as a Blood First Edition Paper on August 8, 2006; DOI 10.1182/blood-2006-02-004531.
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IMMUNOBIOLOGY
Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells
Daniel H. D. Gray,
Natalie Seach,
Tomoo Ueno,
Morag K. Milton,
Adrian Liston,
Andrew M. Lew,
Christopher C. Goodnow, and
Richard L. Boyd
From the Monash Immunology and Stem Cell Laboratories (MISCL), Monash University, Victoria; the John Curtin School of Medical Research, The Australian National University, Canberra; The Australian Phenomics Facility, The Australian National University, Canberra; and the Walter and Eliza Hall Institute, Victoria, Australia.
Despite the importance of thymic stromal cells to T-cell development, relatively little is known about their biology. Here, we use single-cell analysis of stromal cells to analyze extensive changes in the number and composition of thymic stroma throughout life, revealing a surprisingly dynamic population. Phenotypic progression of thymic epithelial subsets was assessed at high resolution in young mice to provide a developmental framework. The cellular and molecular requirements of adult epithelium were studied, using various mutant mice to demonstrate new cross talk checkpoints dependent on RelB in the cortex and CD40 in the medulla. With the use of Ki67 and BrdU labeling, the turnover of thymic epithelium was found to be rapid, but then diminished on thymic involution. The various defects in stromal turnover and composition that accompanied involution were rapidly reversed following sex steroid ablation. Unexpectedly, mature cortical and medullary epithelium showed a potent capacity to stimulate naive T cells, comparable to that of thymic dendritic cells. Overall, these studies show that the thymic stroma is a surprisingly dynamic population and may have a more direct role in negative selection than previously thought.
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