This project's goal is to use a well-characterized model system to define processes governing the formation and activity of CD4+CD25+Foxp3+ regulatory T (Treg) cells. The proposal will make use of existing lineages of transgenic mice expressing the influenza virus hemagglutinin (HA) under the control of a variety of promoters (HA Tg mice) and/or HA-specific T cell receptors with varying affinities and specificities for the HA (TCR Tg mice). By analyzing double transgenic mice co-expressing HA-specific TCRs and neo-self HA peptides (TCRxHA Tg mice), we have shown that highly specific interactions with HA-derived peptides can induce thymocytes to undergo selection to become Treg cells that suppress conventional CD4+ T (Tconv) cell responses in vitro, and can modify immune responses in vivo. We have shown that the formation of these Treg cells is highly sensitive to variations in the amount of the HA that is expressed in different HA Tg lineages, and that expression of HA selectively by antigen presenting cells in one of these lineages (designated HACII mice) induces the spontaneous development of inflammatory arthritis in TCRxHACII mice despite the presence of antigen-specific Treg cells. We will use this unique model system to examine how TCR specificity directs Treg cell formation and determines the capacity of Treg cells to modulate anti-self and anti-viral immune responses.
In Aim 1 we will examine how TCR recognition of self-peptides shapes Treg repertoire formation. We will modulate the reactivity of the TCR for self-peptides and determine the effects on thymic Treg cell development in TCRxHA Tg mice, and will use adoptive transfer approaches to examine the development of Treg cells in the periphery of HA Tg mice under various conditions.
In Aim 2 we will examine how Treg specificity for self-peptides shapes anti-viral immunity. We will analyze the ability of Treg cells from TCRxHA Tg mice to modulate antibody responses to influenza viruses with which they possess varying degrees of crossreactivity, and examine HA Tg mice that do not co-express TCR transgenes for their frequencies of virus- specific CD4+ Treg and Tconv cells.
In Aim 3 we will determine how TCR specificity impacts the ability of Treg cells to prevent autoimmune arthritis. We will either deplete Treg cells, or add Treg cells with varying degrees of reactivity with the HA to pre-arthritic TCRxHACII mice, and determine the effects on cellular processes that accompany arthritis development. We will also analyze the expansion and differentiation of Treg cells with varying degrees of reactivity for the HA following transfer into HACII or TS1xHACII mice. These studies will provide fundamental insights into the mechanisms of immune repertoire formation and tolerance. They will enhance our understanding of the role immune regulation plays in anti-viral immunity and how its failure can contribute to autoimmunity, and will enhance the ability of Treg cells to b exploit in diagnostic therapeutic settings.

Public Health Relevance

Regulatory T cells play an vital role in preventing the immune system from mounting harmful responses to the body's cells and tissues, such as can occur in autoimmune diseases. These cells can also modify the activity of the immune system in settings such as infection, transplantation and cancer. This proposal uses genetically-modified mice to analyze mechanisms and cellular processes than govern the development and activity of regulatory T cells, and to develop novel insights into regulatory T cell biology that will facilitate their application for diagnosis and therapy of human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059166-09
Application #
8240106
Study Section
Special Emphasis Panel (ZRG1-IMM-G (02))
Program Officer
Lapham, Cheryl K
Project Start
2004-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
9
Fiscal Year
2012
Total Cost
$409,927
Indirect Cost
$164,902
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Weissler, Katherine A; Caton, Andrew J (2014) The role of T-cell receptor recognition of peptide:MHC complexes in the formation and activity of Foxp3? regulatory T cells. Immunol Rev 259:11-22
Perng, Olivia A; Aitken, Malinda; Rankin, Andrew L et al. (2014) The degree of CD4+ T cell autoreactivity determines cellular pathways underlying inflammatory arthritis. J Immunol 192:3043-56
Caton, Andrew J; Kropf, Elizabeth; Simons, Donald M et al. (2014) Strength of TCR signal from self-peptide modulates autoreactive thymocyte deletion and Foxp3(+) Treg-cell formation. Eur J Immunol 44:785-93
Caton, Andrew J; Weissler, Katherine A (2014) Regulatory cells in health and disease. Immunol Rev 259:5-10
Bedoya, Felipe; Cheng, Guang-Shing; Leibow, Abigail et al. (2013) Viral antigen induces differentiation of Foxp3+ natural regulatory T cells in influenza virus-infected mice. J Immunol 190:6115-25
Oh, Soyoung; Aitken, Malinda; Simons, Donald M et al. (2012) Requirement for diverse TCR specificities determines regulatory T cell activity in a mouse model of autoimmune arthritis. J Immunol 188:4171-80
Cozzo Picca, Cristina; Simons, Donald M; Oh, Soyoung et al. (2011) CD4?CD25?Foxp3? regulatory T cell formation requires more specific recognition of a self-peptide than thymocyte deletion. Proc Natl Acad Sci U S A 108:14890-5
Simons, Donald M; Caton, Andrew J (2011) Flow cytometric profiling of mature and developing regulatory T cells in the thymus. Methods Mol Biol 707:55-69
Feng, Xiaoming; Ippolito, Gregory C; Tian, Lifeng et al. (2010) Foxp1 is an essential transcriptional regulator for the generation of quiescent naive T cells during thymocyte development. Blood 115:510-8
Simons, Donald M; Picca, Cristina Cozzo; Oh, Soyoung et al. (2010) How specificity for self-peptides shapes the development and function of regulatory T cells. J Leukoc Biol 88:1099-107

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