The maintenance of immune tolerance is critical for the prevention of autoimmunity. A key cell that helps promote immune tolerance is the thymic medullary epithelial cell (mTEC). A critical subset of mTEC's expresses a wide array of tissue restricted antigens under the control of the Autoimmune Regulator (Aire) gene. Aire was identified as the defective gene in the autoimmune syndrome Autoimmune Polyglandular Syndrome Type 1 and highlights the critical importance of this gene and the mTEC cell population for the maintenance of tolerance. The Aire-expressing subset of mTEC's promotes self-tolerance by helping promote the display of TRA's to developing thymocytes for negative selection and perhaps the positive selection of regulatory T cells. Within the thymus, the mTEC compartment appears to be in a state of dynamic turnover, but what molecular pathways and cell populations that are involved in this turnover remain to be determined especially in adulthood after thymic development. In addition to their turnover, the role of mTEC's in the induction and selection of regulatory T cells (Treg's) in the thymus remains to be clearly delineated. Recently, we have developed a powerful set of genetic tools to help dissect and examine the turnover of mTEC's and their control of Treg selection including a cell ablation system and cell fate mapping system. Both systems can be temporally controlled and allow for testing cell turnover dynamics in the adult and neonatal settings. We hypothesize that the mTEC compartment is a dynamic compartment of cells that is regenerated by precursor cells that express Aire and that this cell compartment is also an important contributor to the selection of Treg's. To test these questions our specific aims are: 1) Determine the mechanism(s) of mTEC turnover and regeneration in adult mice, 2) Identify the role of mTECs in guiding regulatory T cell induction and development, and 3) Assess the functional consequences of Aire-expressing cell ablation on the development of autoimmunity. Taken together our studies will help determine what factors and cells contribute to the turnover and replacement of mTEC's, their potential role in the induction of Treg's, and whether the long term maintenance of mTEC's are critical for immune tolerance.

Public Health Relevance

This project is designed to further understand an important cell population in the thymus that helps promote immune tolerance to self called medullary thymic epithelial cells (mTEC's). Defects in mTEC function have been shown to contribute to the development of autoimmunity and further study is needed to understand how this cell population is maintained. The proposed studies will further define how these cells turnover and how they prevent autoimmunity throughout life.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI097457-01
Application #
8221029
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Rothermel, Annette L
Project Start
2011-12-01
Project End
2016-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
1
Fiscal Year
2012
Total Cost
$386,250
Indirect Cost
$136,250
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Khan, Imran S; Mouchess, Maria L; Zhu, Meng-Lei et al. (2014) Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance. J Exp Med 211:761-8
Khan, Imran S; Taniguchi, Ruth T; Fasano, Kayla J et al. (2014) Canonical microRNAs in thymic epithelial cells promote central tolerance. Eur J Immunol 44:1313-9
Metzger, Todd C; Khan, Imran S; Gardner, James M et al. (2013) Lineage tracing and cell ablation identify a post-Aire-expressing thymic epithelial cell population. Cell Rep 5:166-79
Cheng, Mickie H; Anderson, Mark S (2013) Insights into type 1 diabetes from the autoimmune polyendocrine syndromes. Curr Opin Endocrinol Diabetes Obes 20:271-8