Multiple sclerosis (MS) and type 1 diabetes (T1D) are complex genetic diseases where pathogenic T cell autoimmune responses target and destroy self-tissue. However, the presence of T cells reactive to self alone is not sufficient for disease o occur as autoreactive T cells can be found in healthy control subjects;thus various means are available that control unwanted responses. One of the most important mechanisms is the activity of regulatory T cells (Tregs), which arise both in thymus and in the peripheral immune system as a consequence of exposure to antigens. While it was originally thought that Tregs represented a homogenous, end-stage differentiated population, recent data suggest that Tregs exist in immune response-specific subsets, which parallel the Th subsets that they control, can under certain conditions, be reprogrammed to secrete pro-inflammatory cytokines. Thus, Treg adaptation to the inflammatory milieu and chameleon-like propensity to take on Th-like phenotypes is physiologic and a fundamental attribute observed in mouse models. We have recently found that there is an increased frequency of Tregs from MS or T1D patients that secrete IFN-? compared to healthy controls, suggesting that this reprogramming may be present in humans as well and under certain conditions can be involved in the pathogenesis of autoimmune diseases. Thus, one fundamental question, addressed in this proposal is """"""""to determine the mechanisms that generate Th-Tregs in autoimmune diseases and how these cells function in vivo under basal, inflammatory and therapeutic conditions."""""""" In addition, the induction and effectiveness of Treg responses are affected by their anatomic location. Factors that have central roles in Treg homeostasis such as TGF-?, IL-6 and others, are expressed differently at mucosal surfaces, in the CNS, and in the pancreas, and may affect Treg differentiation locally. Thus, in this proposal we will address a second hypothesize that """"""""the anatomic location and immune environment of Tregs dictates their pathway of differentiation in humans and that these processes are altered in individuals prone to autoimmunity."""""""" The following aims represent a concerted effort between two centers that will allow us to address these questions using the same experimental and disease platforms. 1. To determine what mechanisms are involved in the differentiation and stability of Th-like Treg subsets in healthy individuals and patients with MS and T1D. 2. To determine whether innate factors, driven by TLR ligation modulate Th-like Tregs. 3. To determine the function of human Th-like Tregs in vivo and the effects of immune therapies in humans and humanized mouse models. These studies will identify wide-ranging and disease-specific features of Th-Tregs in autoimmunity, and, hopefully, identify novel mechanisms that are important for prevention of MS, T1D, and potentially other autoimmune diseases. In addition, these studies may identify pathways that may be targeted by existing or novel immune therapeutics.
Multiple sclerosis (MS) and type 1 diabetes (T1D) are complex genetic diseases where pathogenic T cell autoimmune responses target and destroy self-tissue. It is now believed that defects in a population of cells with immunosuppressive properties called regulatory T cells are central to the development of autoimmune diseases, but many facets of the biology of these cells in humans are still unknown. In this project, we will pursue efforts to determine how these cells are generated in health and disease and identify key molecules that could be targeted therapeutically to restore normal processes in MS and T1D.
|DuPage, Michel; Bluestone, Jeffrey A (2016) Harnessing the plasticity of CD4(+) T cells to treat immune-mediated disease. Nat Rev Immunol 16:149-63|
|Tooley, James E; Vudattu, Nalini; Choi, Jinmyung et al. (2016) Changes in T-cell subsets identify responders to FcR-nonbinding anti-CD3 mAb (teplizumab) in patients with type 1 diabetes. Eur J Immunol 46:230-41|
|Wilcox, Nicholas S; Rui, Jinxiu; Hebrok, Matthias et al. (2016) Life and death of Î² cells in Type 1 diabetes: A comprehensive review. J Autoimmun 71:51-8|
|Garyu, Justin W; Meffre, Eric; Cotsapas, Chris et al. (2016) Progress and challenges for treating Type 1 diabetes. J Autoimmun 71:1-9|
|Durning, Sean P; Preston-Hurlburt, Paula; Clark, Paul R et al. (2016) The Receptor for Advanced Glycation Endproducts Drives T Cell Survival and Inflammation in Type 1 Diabetes Mellitus. J Immunol 197:3076-3085|
|Matheu, Melanie P; Othy, Shivashankar; Greenberg, Milton L et al. (2015) Imaging regulatory T cell dynamics and CTLA4-mediated suppression of T cell priming. Nat Commun 6:6219|
|Fuhrman, Christopher A; Yeh, Wen-I; Seay, Howard R et al. (2015) Divergent Phenotypes of Human Regulatory T Cells Expressing the Receptors TIGIT and CD226. J Immunol 195:145-55|
|Vander Heiden, Jason A; Yaari, Gur; Uduman, Mohamed et al. (2014) pRESTO: a toolkit for processing high-throughput sequencing raw reads of lymphocyte receptor repertoires. Bioinformatics 30:1930-2|
|Manzel, Arndt; Muller, Dominik N; Hafler, David A et al. (2014) Role of ""Western diet"" in inflammatory autoimmune diseases. Curr Allergy Asthma Rep 14:404|
|Kofler, David M; Marson, Alexander; Dominguez-Villar, Margarita et al. (2014) Decreased RORC-dependent silencing of prostaglandin receptor EP2 induces autoimmune Th17 cells. J Clin Invest 124:2513-22|
Showing the most recent 10 out of 22 publications