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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Special Emphasis Panel (ZRG1-IMM-C (52))
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Johnson, David R
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Children's Hospital Boston
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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
Noval Rivas, Magali; Chatila, Talal A (2016) Regulatory T cells in allergic diseases. J Allergy Clin Immunol 138:639-52
Charbonnier, Louis-Marie; Wang, Sen; Georgiev, Peter et al. (2015) Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling. Nat Immunol 16:1162-73
Sheikine, Yuri; Woda, Craig B; Lee, Pui Y et al. (2015) Renal involvement in the immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) disorder. Pediatr Nephrol 30:1197-202
Noval Rivas, Magali; Burton, Oliver T; Wise, Petra et al. (2015) Regulatory T cell reprogramming toward a Th2-cell-like lineage impairs oral tolerance and promotes food allergy. Immunity 42:512-23
Charbonnier, Louis-Marie; Janssen, Erin; Chou, Janet et al. (2015) Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA. J Allergy Clin Immunol 135:217-27
Wang, Sen; Charbonnier, Louis-Marie; Noval Rivas, Magali et al. (2015) MyD88 Adaptor-Dependent Microbial Sensing by Regulatory T Cells Promotes Mucosal Tolerance and Enforces Commensalism. Immunity 43:289-303
Sreedharan, Rajasree; Chen, Shaoying; Miller, Melody et al. (2014) Mice with an absent stress response are protected against ischemic renal injury. Kidney Int 86:515-24
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
Keles, Sevgi; Jabara, Haifa H; Reisli, Ismail et al. (2014) Plasmacytoid dendritic cell depletion in DOCK8 deficiency: rescue of severe herpetic infections with IFN-α 2b therapy. J Allergy Clin Immunol 133:1753-5.e3

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