CD4+CD25+ regulatory T (Treg) cells express the forkhead transcription factor Foxp3 and are essential for the maintenance of dominant immunological tolerance to the 'extended self, which includes self proteins and the commensal microbial flora. Global failure of T reg cells due to mutations in Foxp3 results in a lethal syndrome of systemic autoimmunity, Iymphoproliferation, and allergic dysregulation, underscoring the essential contribution of T reg cells to the control of immune responses. There are two types of Treg cells, the so called 'natural'T reg (nT reg) cells that arise as a specific lineage in the thymus, and 'induced'T reg (iTreg) cells that are generated from conventional T cells in the periphery. The broad, long- term objective of this project is to elucidate the fundamental mechanisms underpinning Treg cell maturation and function.
The specific aims of this proposal are intended to identify the individual contributions of iT reg and nTreg cells to tolerance and to dissect the mechanisms responsible for functional distinctions between the two cell types. The proposed studies will test the hypothesis that complete tolerance requires both iTreg and nT reg cells. We postulate that each cell type serves a non-redundant and synergistic role, mandated by distinct TCR repertoires, variations in gene expression patterns, and divergent functional attributes. In the proposed experiments, we will use thymic organ cultures to establish the TCR affinity requirements that control nT reg selection in the thymus. We will employ incisive genetic tools to functionally define the iTreg and nT reg cell populations used to rescue Foxp3 deficient mice and mice with inflammatory bowel disease by adoptive transfer immunotherapy. These investigations will provide fundamental and preclinical insights into mechanisms governing the maintenance of dominant tolerance by Treg cells, as well as the dysregulated immune responses and autoimmunity unleashed by Treg cell deficiency.

Public Health Relevance

A healthy immune system requires two types of regulatory T (T reg) cells that depend upon expression of the gene Foxp3;the 'natural'Treg (nT reg) cells that arise in thymus and 'induced'Treg (iT reg) cells that are generated in the other lymphoid organs like the lymph nodes and spleen. The proposed research will identify the molecular basis for the synergistic, non-redundant role that each cell type plays in maintaining a state of immune tolerance, where all elements of the immune system act in concert to prevent infection while avoiding damage to vital organs. Genetic and environmental factors that diminish either type of T reg cell influence are likely to be important contributors to chronic autoimmune conditions (e.g. inflammatory bowel disease and arthritis), and the rational design of T reg cell-directed therapy aimed at curing these disorders depends upon this information.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI073731-01A2S1
Application #
8079347
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Lapham, Cheryl K
Project Start
2010-07-12
Project End
2011-06-30
Budget Start
2010-07-12
Budget End
2011-06-30
Support Year
1
Fiscal Year
2010
Total Cost
$207,923
Indirect Cost
Name
Medical College of Wisconsin
Department
Pediatrics
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Haribhai, Dipica; Chatila, Talal A; Williams, Calvin B (2016) Immunotherapy with iTreg and nTreg Cells in a Murine Model of Inflammatory Bowel Disease. Methods Mol Biol 1422:197-211
Haribhai, Dipica; Luo, Xiaofeng; Chen, Juan et al. (2016) TGF-?1 along with other platelet contents augments Treg cells to suppress anti-FVIII immune responses in hemophilia A mice. Blood Adv 1:139-151
Haribhai, Dipica; Ziegelbauer, Jennifer; Jia, Shuang et al. (2016) Alternatively Activated Macrophages Boost Induced Regulatory T and Th17 Cell Responses during Immunotherapy for Colitis. J Immunol 196:3305-17
Schmitt, Erica G; Williams, Calvin B (2013) Generation and function of induced regulatory T cells. Front Immunol 4:152
Mayne, Christopher G; Williams, Calvin B (2013) Induced and natural regulatory T cells in the development of inflammatory bowel disease. Inflamm Bowel Dis 19:1772-88
Schmitt, Erica G; Haribhai, Dipica; Jeschke, Jonathan C et al. (2013) Chronic follicular bronchiolitis requires antigen-specific regulatory T cell control to prevent fatal disease progression. J Immunol 191:5460-76
Schmitt, Erica G; Haribhai, Dipica; Williams, Jason B et al. (2012) IL-10 produced by induced regulatory T cells (iTregs) controls colitis and pathogenic ex-iTregs during immunotherapy. J Immunol 189:5638-48
Relland, Lance M; Williams, Jason B; Relland, Gwendolyn N et al. (2012) The TCR repertoires of regulatory and conventional T cells specific for the same foreign antigen are distinct. J Immunol 189:3566-74
Rivas, Magali Noval; Koh, Yi T; Chen, Andrew et al. (2012) MyD88 is critically involved in immune tolerance breakdown at environmental interfaces of Foxp3-deficient mice. J Clin Invest 122:1933-47
Peng, I-Chen; Chen, Zhen; Sun, Wei et al. (2012) Glucagon regulates ACC activity in adipocytes through the CAMKK?/AMPK pathway. Am J Physiol Endocrinol Metab 302:E1560-8

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