The thymus is a specialized organ for the development of T cells. Within the thymus, cortical epithelial cells play a crucial role in the generation of T cells with appropriate specificity and function. In this project, we will study the role of a gene expressed uniquely in cortical epithelial cells, 25t, which is involved in proteolysis and is required for positive selection of CD8 T cells. We will further define and study key cortical epithelial cell identify genes by creating reporter mice to facilitate the purification or depletion of these cells in vivo. We will also determine if 25T and other genes are altered in situations where T cell development is impaired, and determine if manipulation of these genes can be used to support T cell reconstitution in vitro. Another focus of this proposal is to define the genetic changes required for the functional maturation that occurs after positive selection. Specifically, we will determine: what gene changes occur at the semi-mature to mature SP transition, which changes are critical for development of proliferation competence, and if specific stromal cell interactions are required for competence

Public Health Relevance

The thymus is a specialized organ for the development of T cells. Within this organ, cortical epithelial cells play a crucial role in the generation of T cells with appropriate specificity and function. This application proposes to explore the molecular mechanisms by which cortical epithelial cells support T cell differentiation, and to exploit this knowledge in developing an in vitro T cell reconstitution system that can be used for therapeutic purposes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI088209-05
Application #
8648988
Study Section
Special Emphasis Panel (ZRG1-IMM-H (02))
Program Officer
Prabhudas, Mercy R
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
5
Fiscal Year
2014
Total Cost
$365,450
Indirect Cost
$117,950
Name
University of Minnesota Twin Cities
Department
Pathology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Mahmud, Shawn A; Manlove, Luke S; Schmitz, Heather M et al. (2014) Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat Immunol 15:473-81
Hogquist, Kristin A; Jameson, Stephen C (2014) The self-obsession of T cells: how TCR signaling thresholds affect fate 'decisions' and effector function. Nat Immunol 15:815-23
Klein, Ludger; Kyewski, Bruno; Allen, Paul M et al. (2014) Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat Rev Immunol 14:377-91
Xing, Yan; Hogquist, Kristin A (2014) Isolation, identification, and purification of murine thymic epithelial cells. J Vis Exp :e51780
Xing, Yan; Jameson, Stephen C; Hogquist, Kristin A (2013) Thymoproteasome subunit-?5T generates peptide-MHC complexes specialized for positive selection. Proc Natl Acad Sci U S A 110:6979-84