Pro-inflammatory Th1 and Th17 T-lymphocytes orchestrate many organ-specific autoimmune diseases, such as multiple sclerosis (MS) and type I diabetes. The pathologic activity of these cells can be modulated by different forms of regulatory T lymphocytes (Treg), most prominently Treg expressing the Foxp3 transcription factor. Adoptive immunotherapy with Foxp3+ Treg therefore holds promise in the selective treatment of autoimmune conditions. Our laboratory has specifically focused on the therapeutic application of Foxp3+ Treg that are generated by conditioning naove T lymphocytes with TGF-2. We demonstrated that the cellular properties of these "induced Treg" (iTreg) differ from those of directly isolated endogenous Treg (natural Treg, nTreg). Despite this, iTreg and nTreg are equivalently potent in treating a model autoimmune disease, experimental allergic encephalomyelitis (EAE), and operate through similar mechanisms. In this proposal, we will address the unique biology of iTreg, and lay a foundation for their clinical translation into a cellular immunotherapeutic. In preliminary studies we demonstrated that a large proportion of iTreg, but not nTreg, lose Foxp3 expression after adoptive transfer. One key difference between iTreg and nTreg is in their extent of self-specificity. Self-specificity will impact T-cell homeostasis, and we hypothesize will also influence iTreg survival and function.
In Aim 1, we will study the role of TCR specificity in iTreg survival, Foxp3 preservation, and therapeutic activity. Our preliminary data shows that iTreg, like nTreg, are highly potent, operate to prevent and treat EAE in an IL-10-dependent manner, and catalyze the development of additional autoantigen-specific Treg (infectious tolerance).
In Aim 2, we will determine how iTreg induce immune tolerance by diverting a pathologic immune response into a regulatory response, and the specific role of IL-10 in this. We have further demonstrated that TLR ligands dramatically enhance the preservation of Foxp3 expression in and survival of therapeutically transferred iTreg. We hypothesize that TLR activation, either through APC or directly into iTreg, promotes the survival and activity of iTreg.
In Aim 3, we will identify how innate immune pathways alter iTreg therapeutic activity, and probe a possible adjunct role for TLR agonists in iTreg induction and immunotherapy. These studies will provide new insights into how iTreg modulate immunity after therapeutic transfer and how they may be functionally optimized to maximum potency and efficacy, and will facilitate the clinical translation of iTreg immunotherapy

Public Health Relevance

diseases develop when the immune system fails to recognize an individual's own cells and tissues as self, and attacks them. Effector T-lymphocytes, a class of cells within the immune system, are critically involved in orchestrating autoimmune responses and mediating tissue damage. This proposal's goal is to promote the development of new cellular therapies for autoimmune diseases using a different class of T lymphocytes, called regulatory T lymphocytes that are able to specifically suppress effector T lymphocyte functions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI056153-09
Application #
8241096
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Esch, Thomas R
Project Start
2003-07-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
9
Fiscal Year
2012
Total Cost
$411,642
Indirect Cost
$166,617
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Zhao, Yunqian; Nguyen, Phuong; Vogel, Peter et al. (2016) Autoimmune susceptibility imposed by public TCRβ chains. Sci Rep 6:37543
Jones, Lindsay L; Alli, Rajshekhar; Li, Bofeng et al. (2016) Differential T Cell Cytokine Receptivity and Not Signal Quality Distinguishes IL-6 and IL-10 Signaling during Th17 Differentiation. J Immunol 196:2973-85
Zhao, Yunqian; Nguyen, Phuong; Ma, Jing et al. (2016) Preferential Use of Public TCR during Autoimmune Encephalomyelitis. J Immunol 196:4905-14
Gurung, Prajwal; Li, Bofeng; Subbarao Malireddi, R K et al. (2015) Chronic TLR Stimulation Controls NLRP3 Inflammasome Activation through IL-10 Mediated Regulation of NLRP3 Expression and Caspase-8 Activation. Sci Rep 5:14488
O'Hear, Carol; Heiber, Joshua F; Schubert, Ingo et al. (2015) Anti-CD33 chimeric antigen receptor targeting of acute myeloid leukemia. Haematologica 100:336-44
Li, Bofeng; Gurung, Prajwal; Malireddi, R K Subbarao et al. (2015) IL-10 engages macrophages to shift Th17 cytokine dependency and pathogenicity during T-cell-mediated colitis. Nat Commun 6:6131
Ray, Avijit; Basu, Sreemanti; Gharaibeh, Raad Z et al. (2015) Gut Microbial Dysbiosis Due to Helicobacter Drives an Increase in Marginal Zone B Cells in the Absence of IL-10 Signaling in Macrophages. J Immunol 195:3071-85
Li, B; Alli, R; Vogel, P et al. (2014) IL-10 modulates DSS-induced colitis through a macrophage-ROS-NO axis. Mucosal Immunol 7:869-78
Tauro, Sharyn; Nguyen, Phuong; Li, Bofeng et al. (2013) Diversification and senescence of Foxp3+ regulatory T cells during experimental autoimmune encephalomyelitis. Eur J Immunol 43:1195-207
Geiger, Terrence L; Tauro, Sharyn (2012) Nature and nurture in Foxp3(+) regulatory T cell development, stability, and function. Hum Immunol 73:232-9

Showing the most recent 10 out of 33 publications