Mucosal surfaces are continuously exposed to harmless foreign antigens such as those from food and commensal bacteria, referred to as environmental antigens. The immune system should be tolerant to these environmental antigens, much as it is to self-antigens. While some mechanisms that regulate tolerance to self and environmental antigens may be shared, others may be unique. We have identified an E3 ubiquitin ligase adaptor, known as Nedd4-family interacting protein 1 (Ndfip1), that regulates T cell tolerance to environmental antigens in mice and man. We recently showed that mice lacking Ndfip1 develop atopic inflammation in lung, skin and GI tract. Additionally, using single nucleotide polymorphism (SNP) analysis, we have identified polymorphisms within the locus that encodes Ndfip1 (located on human Chr5) that are more common in patients with asthma, atopic dermatitis (AD) and inflammatory bowel disease (IBD)2, thus supporting that Ndfip1 regulates atopic disease in both mice and man. Studying Ndfip1-/- mice, we have determined that T cells lacking Ndfip1 become activated and produce Th2 cytokines in response to environmental antigens. We hypothesize that Ndfip1 regulates T cell tolerance by promoting the differentiation of na?ve T cells into iTregs and by inducing antigen-unresponsiveness. In this proposal, we will 1) determine the mechanism by which Ndfip1 promotes iTreg differentiation by determining whether Ndfip1 is required for iTreg conversion in vitro and in vivo and resolving whether the defect in iTreg conversion of Ndfip1-/- T cells is cell intrinsic or due to their production of IL-4. We will also establish whether Ndfip1 is required for Itch ubiquitylation of TIEG1. We will also 2) test whether Ndfip1-/- T cells require CD28-costimulation to become activated in vivo, use altered peptide ligands in vivo and in vitro to establish whether Ndfip1-/- T cells are activated by lower affinity antigens than WT cells, and determine whether Ndfip1 promotes antigen unresponsiveness in wild type na?ve T cells by dampening TCR or IL-2R signaling. Finally, we will establish the mechanism(s) underlying these defects. We believe that Ndfip1-dependent pathways could be targeted therapeutically to treat atopic inflammatory diseases such as asthma as well as T cell mediated autoimmune disease. A long-term goal of the laboratory is to design pharmacological mimics of Ndfip1 that would promote its functions therapeutically. The studies we propose will help us toward this goal.

Public Health Relevance

In this proposal, we will determine whether and how Ndfip1 regulates T cell tolerance to environmental antigens. Understanding how this works on a mechanistic level could have broad impact to food allergy and mucosal immunity and to atopic diseases in general. Thus, we believe that Ndfip1-dependent pathways could be targeted therapeutically to treat atopic inflammatory diseases such as asthma, food allergy and atopic dermatitis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Transplantation, Tolerance, and Tumor Immunology (TTT)
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Rothermel, Annette L
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Children's Hospital of Philadelphia
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Moser, Emily K; Field, Natania S; Oliver, Paula M (2018) Aberrant Th2 inflammation drives dysfunction of alveolar macrophages and susceptibility to bacterial pneumonia. Cell Mol Immunol 15:480-492
Layman, Awo Akosua Kesewa; Deng, Guoping; O'Leary, Claire E et al. (2017) Ndfip1 restricts mTORC1 signalling and glycolysis in regulatory T cells to prevent autoinflammatory disease. Nat Commun 8:15677
Layman, Awo Akosua; Sprout, Stephanie; Phillips, Dylan et al. (2017) Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production. Sci Rep 7:39649
Layman, Awo A K; Oliver, Paula M (2016) Ubiquitin Ligases and Deubiquitinating Enzymes in CD4+ T Cell Effector Fate Choice and Function. J Immunol 196:3975-82
Riling, Christopher; Kamadurai, Hari; Kumar, Suresh et al. (2015) Itch WW Domains Inhibit Its E3 Ubiquitin Ligase Activity by Blocking E2-E3 Ligase Trans-thiolation. J Biol Chem 290:23875-87
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Ramos-Hernández, Natalia; Ramon, Hilda E; Beal, Allison M et al. (2013) Ndfip1 enforces a requirement for CD28 costimulation by limiting IL-2 production. J Immunol 191:1536-46
Sun, Jianbo; Keim, Celia D; Wang, Jiguang et al. (2013) E3-ubiquitin ligase Nedd4 determines the fate of AID-associated RNA polymerase II in B cells. Genes Dev 27:1821-33
Ramon, Hilda E; Beal, Allison M; Liu, Yuhong et al. (2012) The E3 ubiquitin ligase adaptor Ndfip1 regulates Th17 differentiation by limiting the production of proinflammatory cytokines. J Immunol 188:4023-31

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