Multiple sclerosis (MS) is characterized by inflammation of the central nervous system (CNS) primarily caused by autoreactive CD4 T cells. It is well documented that myelin-specific T cells, especially Th1 cells and Th17 cells, are important in the initiation of tissue inflammation in experimental autoimmune encephalomyelitis (EAE), the animal model of MS. A subset of CD4 T cells called CD4+CD25+ regulatory T cells (Tregs) that express Forkhead box P3 (Foxp3) can control autoimmune responses. During EAE development, Tregs enter the inflammation site in the CNS but are unable to suppress autoreactive CD4 T cells. It remains elusive, however, how Tregs are regulated during CNS inflammation. Our laboratory preliminary results indicate Tregs in the absence of STAT3 are capable of infiltrating CNS more effectively and therefore reduce chronic inflammation and EAE symptoms better than Tregs in the presence of STAT3. The following specific aims are proposed to elucidate the pathological role of STAT3 in the regulation of Tregs? function and the underlying mechanisms, and to understand the regulatory molecules of STAT3 activation in Tregs during CNS inflammation.
Aim 1 : To determine the impact of STAT3 expression on regulatory T cell function during CNS inflammation.
Aim 2 : To define the mechanism by which STAT3 expression in Tregs prevents CNS accumulation of Tregs during inflammation.
Aim 3 : To determine the environmental cues mediating STAT3 activation for Tregs during CNS inflammation. Collectively, these studies are designed to provide new information regarding the cellular mediators of CNS inflammation during EAE and will help to define the properties and molecular regulators that control the development of Tregs during CNS inflammation. Our overarching goal is to understand the regulatory network of inflammatory molecules and Tregs in promoting chronic inflammatory disorders, such as MS. Such data will help to identify molecular targets that can be used for potential therapeutic strategies for the treatment of autoimmune disease.

Public Health Relevance

Autoimmune diseases are characterized by aberrant activation of pathogenic CD4 helper T cells. Regulatory T cells, a subset of CD4 helper T cells, suppress the development of autoimmune disease, and we are interested in defining the cellular and molecular pathways for their activity. This proposal aims at establishing novel strategies for regulatory T cell modulation and new therapeutic avenues for the treatment of autoimmune disease involving inflammation of the central nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI127997-02
Application #
9403228
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Esch, Thomas R
Project Start
2016-12-16
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Microbiology/Immun/Virology
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030