Naturally occurring Foxp3+ regulatory T (Treg) cells play an important role in the maintenance of immune homeostasis and prevention of autoimmunity. Although it is commonly thought that self-reactivity is important for Treg cell selection, the quantitative parameters that govern this process has not been reported. In this proposal, we will analyze the role of TCR self-reactivity in thymic Treg cell differentiation as wel as negative selection.
In Aim 1, we will study these thymic tolerance mechanisms using a novel panel of TCRs with broad reactivity to ovalbumin peptide (OVA323-339). If self-reactivity is the primary driving force for thymic Treg cell development as suggested by our preliminary data, then the antigens presented in the thymus will determine the Treg cell repertoire.
In Aim 2, we will address whether the thymic APC subsets serve non-redundant capacities in Treg cell generation and negative selection. Finally, we will assess in Aim 3 whether the level of self-reactivity that triggers thymic tolerance mechanisms also triggers peripheral Treg cell generation. We will also assess the degree of self-reactivity needed for Treg cells to prevent autoimmunity, as well as for effector cells to cause pathology. Understanding the mechanisms that govern Treg cell development may lead to the development of therapies which utilize Treg cell-mediated therapies for the treatment of autoimmune disease.

Public Health Relevance

Regulatory T cells are a subset of immune cells which are potent inhibitors of immune inflammation. Their normal role is to prevent the spontaneous development of autoimmune disease. Our goal is to understand the mechanisms by which regulatory T cell normally develop, with the notion that this information can help in the design of therapies which enhance the generation of regulatory T cells to treat autoimmune disease.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI079187-07
Application #
8704100
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Prabhudas, Mercy R
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Perry, Justin S A; Lio, Chan-Wang J; Kau, Andrew L et al. (2014) Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus. Immunity 41:414-26
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Lio, Chan-Wang J; Dodson, Lindzy F; Deppong, Christine M et al. (2010) CD28 facilitates the generation of Foxp3(-) cytokine responsive regulatory T cell precursors. J Immunol 184:6007-13
Bautista, Jhoanne L; Lio, Chan-Wang J; Lathrop, Stephanie K et al. (2009) Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nat Immunol 10:610-7
Lee, Hyang Mi; Hsieh, Chyi-Song (2009) Rare development of Foxp3+ thymocytes in the CD4+CD8+ subset. J Immunol 183:2261-6