CD4+Foxp3+ regulatory T (TR) cells are crucial to the maintenance of peripheral tolerance. Natural regulatory T (nTR) lymphocytes are a distinct thymus-derived lineage. A second subset of induced Foxp3+ regulatory T (iTR) cells can be generated de novo from conventional CD4+Foxp3- T cells upon antigenic stimulation in the presence of TGF-beta and IL-2. While both nTR and iTR cells are dependent on the expression of the forkhead transcription factor Foxp3 for their differentiation and suppressive action, the two populations are molecularly and functionally distinct. In both humans and in mice, the failure of TR cells to differentiate due to loss of function mutations in Foxp3 results in a lethal disease of systemic autoimmunity, lympho-proliferation and allergic dysregulation. Foxp3 mutations also result in the accumulation of TR cell precursors that have failed to differentiate into functional TR cells in tissues targeted by the autoimmune inflammatory process. These cells, which are predicted to be autoreactive, are highly proliferative and actively produce large amounts of cytokines and granzymes, and thus may contribute to disease pathology. Our recent studies on Foxp3-deficient mice revealed that the disease can be dissociated into two main components: one that is dependent on the innate immune regulator MyD88 and which involves inflammation at the mucosal surfaces in the skin, gut and lungs, and another that is MyD88-independent, manifesting as unrestrained systemic lympho- and myelo-proliferation. Whether this dichotomy reflects a division of labor between nTR and iTR cells or reflects the utilization of distinct TR cell effector molecules such as IL-10 and CTLA-4 remains unclear. Our long-term goal is to dissect the role of Foxp3-regulated pathways in the induction and maintenance of immunologic tolerance. The focus of this proposal is to identify key cellular and molecular mechanisms by which Foxp3 deficiency promotes autoimmunity and inflammation. We hypothesize that Foxp3 deficiency unleashes unrestrained activation of both the innate and the adaptive immune responses, driven by the regulatory failure of both nTR and iTR cells. Furthermore, we hypothesize that the aborted TR cell precursors seen in Foxp3 deficiency represent a unique class of tissue-specific autoimmune effector cells that contributes to disease pathogenesis and tissue damage. The proposed studies will provide fundamental insights into the pathogenesis of diseases associated with TR cell deficiency and will enable novel therapeutic approaches employing TR cell-based interventions.

Public Health Relevance

Regulatory T cell (TR) deficiency disorders encompass a number of heritable immunological diseases characterized by disproportionate immune responses to disease and environmental agents (e.g. bacteria, allergens, vaccines) and to self tissues, leading to allergic, autoimmune and inflammatory sequelae that are life threatening or fatal. Many individuals suffering from TR cell deficiency have mutations in the transcription factor FOXP3, which controls the differentiation and the function of TR cells. We are proposing to elucidate the mechanisms by which FOXP3 mutations induce disease, and explore the capacity of therapy with TR cells to rescue the disease manifestations. Our studies would uncover novel mechanisms by which the immune system regulates diseases of allergy, inflammation and autoimmunity, and will help identify novel therapeutic approaches relevant to both these disorder and the more common allergic inflammatory and autoimmune diseases in the general population.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI085090-06
Application #
8585020
Study Section
Special Emphasis Panel (ZRG1-IMM-C (52))
Program Officer
Johnson, David R
Project Start
2009-12-10
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
6
Fiscal Year
2014
Total Cost
$364,614
Indirect Cost
$83,949
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Burton, Oliver T; Noval Rivas, Magali; Zhou, Joseph S et al. (2014) Immunoglobulin E signal inhibition during allergen ingestion leads to reversal of established food allergy and induction of regulatory T cells. Immunity 41:141-51
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Verbsky, James W; Chatila, Talal A (2013) Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases. Curr Opin Pediatr 25:708-14
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
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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Haribhai, Dipica; Williams, Jason B; Jia, Shuang et al. (2011) A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity 35:109-22
Verbsky, James W; Chatila, Talal A (2011) T-regulatory cells in primary immune deficiencies. Curr Opin Allergy Clin Immunol 11:539-44

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