T regulatory cells (Tregs) play a critical role in controlling organ-specific autoimmune diseases, including type 1 diabetes, multiple sclerosis, and vitiligo. Most studies that address Treg function are performed in vitro or in secondary lymphoid organs (SLOs), and little is known about how Tregs function within peripheral tissues. Tregs must first identify the correct tissue, find the focus of inflammation, and then co-localize with effector T cells (Teffs), yet how this is done efficiently in peripheral tissues is unknown. Te central hypothesis in this proposal is that Tregs require chemokine signals and tissue-specific dendritic cell interactions to find and regulate Teffs within peripheral tissues. These mechanisms cannot be appropriately studied outside of peripheral tissues, and therefore require an in vivo model of organ-specific autoimmunity to define them. We created a mouse model of the autoimmune skin disease vitiligo, in which CXCL10 is required to direct Teff migration into skin and epidermis to drive disease. We have extensively developed this model using genetically modified mice, skin flow cytometry, and confocal microscopy, correlating our observations to human tissues in order to better understand T cell function during autoimmunity. To test our hypothesis, we will perform functional studies in our mouse model of vitiligo and correlate these findings to an existing biobank of human vitiligo skin samples. We found that Tregs suppress vitiligo and localize to CXCL10 in our mouse model. We hypothesize that Tregs are recruited by CXCL10 to co-localize with Teffs and suppress their function. We will test this in Aim 1, where we will determine whether Tregs migrate with Teffs, if they require the CXCL10 receptor CXCR3, and whether human Treg localization in the skin predicts vitiligo severity. We found that Langerhans cells (LHCs) are major producers of CXCL10 in the skin during vitiligo, are required for epidermal Treg accumulation, and for control of disease. We hypothesize that Tregs and Teffs require tethering to LHCs through TCR-MHC interactions and CXCL10 to promote their co-localization. We will test this in Aim 2, where we will determine whether Teff/Treg interactions with LHCs is antigen-specific, whether CXCL10 stabilizes their interaction, and how frequently Teff-Treg-LHC interactions occur in human vitiligo skin. In the absence of Tregs or LHCs, Teffs accumulate in large numbers in the skin during vitiligo, independent of proliferation. We hypothesize that Tregs directly promote Teff egress from the skin. We will test this in Aim 3, where we will define the phenotype of Teffs after suppression by Tregs, determine whether Tregs promote Teff egress from the skin, and correlate the immunophenotype of regulated Teffs in mouse and human vitiligo. Vitiligo serves as an ideal model to investigate fundamental mechanisms by which Tregs suppress Teffs within peripheral tissues during autoimmunity. This work has the potential to define pathways that can be targeted as a new treatment strategy for multiple organ-specific autoimmune diseases.

Public Health Relevance

Autoimmune diseases that affect specific organs of the body, including type 1 diabetes, multiple sclerosis, inflammatory bowel disease, thyroid disease, and vitiligo, are devastating for patients. The body has natural mechanisms to control these diseases, which could be used to develop new treatment strategies, but very little is known about how they work. Our goal in this proposal is to learn how autoimmunity is controlled by the body in order to develop better treatments that promote these natural protective responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR069114-01
Application #
9009087
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
Project Start
2015-09-15
Project End
2020-07-31
Budget Start
2015-09-15
Budget End
2016-07-31
Support Year
1
Fiscal Year
2015
Total Cost
$368,500
Indirect Cost
$148,500
Name
University of Massachusetts Medical School Worcester
Department
Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Rashighi, Mehdi; Harris, John E (2017) Vitiligo Pathogenesis and Emerging Treatments. Dermatol Clin 35:257-265
Vanderweil, Stefan G; Amano, Shinya; Ko, Wei-Che et al. (2017) A double-blind, placebo-controlled, phase-II clinical trial to evaluate oral simvastatin as a treatment for vitiligo. J Am Acad Dermatol 76:150-151.e3
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