- PROJECT 2 Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS) associated with increases in activated myelin-reactive T cells. We have previously identified immunoregulatory defects in patients including loss of CD4+Foxp3+ regulatory T cells (Tregs), and a decrease in expression of TIM-3 on CD4 T cells. TIM-3 is selectively expressed on Th1 cells, and engagement of TIM-3 by its ligands galectin-9 or the recently discovered CEACAM-1 regulates Th1 cells and controls tolerance induction. Blocking the TIM-3/CEACAM-1 pathway exacerbates disease in a mouse model for MS. The mechanisms underlying the loss of TIM-3 in MS are not known. We recently undertook a transcriptional profiling study from PBMC of MS patients and identified two subsets of MS patients (MSA and MSB), with MSA patients showing a more active disease. Our preliminary data indicate that lower expression of TIM-3 distinguished the MSA group. Furthermore, a beneficial response to interferon- (IFN) therapy correlated with the degree that TIM-3 was upregulated. Additional experiments identified IFN and IL-27, which can be induced by IFN in APCs, as major inducers of TIM-3 on T cells. Taken together with recent reports showing low IFN serum levels in patients, this suggests that a defect in the IFN-TIM-3 pathway may play a part in the development of MS. Moreover, our preliminary studies show that TIM-3 is upregulated on human Tregs after activation and that TIM-3+ Tregs are more efficient suppressors than TIM-3- Tregs. Thus, the previously reported loss of Treg function in MS patients that disappeared with IFN treatment may be linked to defective TIM-3 expression. Our overall hypothesis is that a genetically mediated loss of type I IFN signal in MS drives a loss of TIM-3 expression and of immunoregulation. We propose studies in both humans and mouse models to accomplish the following aims: 1. To determine the mechanism by which IFN and IL-27 regulate TIM-3 expression and IL-10 secretion by effector T cells. 2. To define the role of TIM-3+ Tregs in regulating autoimmunity in the CNS. These investigations provide a link between the genetic variations underlying autoimmune disease with functional alterations in immune function.

Public Health Relevance

- PROJECT 2 Multiple Sclerosis (MS) is an autoimmune disease resulting from the attack of the central nervous system by the body's own T cells. Many of the genes and proteins involved in disease are unknown. We propose to determine how certain molecules involved in a cascade of reactions in T cells (involving IFN, IL-27, TIM-3 and IL-10) influence the development of MS, which may lead to better therapeutic options for patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI073748-10
Application #
9707708
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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