DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Effect of Commensal Bacteria on the Development of Encephalitogenic T Cells

Principal Investigator: ITO, KOUICHI
Institution Receiving Award: RUTGERS, NEW JERSEY, STATE UNIVERSITY OF
Program: MSRP
Proposal Number: MS110174
Award Number: W81XWH-12-1-0404
Funding Mechanism: Idea Award
Partnering Awards:
Award Amount: $694,706.00


PUBLIC ABSTRACT

Multiple sclerosis (MS) is an autoimmune disease that causes nerve damage in the brain and spinal cord. Although T cells that recognize the myelin sheath surrounding nerve fibers have been suggested to initiate the disease, it is still unknown how the pathogenic T cells develop in MS patients. Recent studies indicated that precursor cells of pathogenic T cells develop in the thymus and migrate into the peripheral lymphoid organs and gut, and further differentiate into pathogenic T cells that are believed to cause MS. Interestingly, self-antigen-reactive T cells differentiate into pathogenic T cells at a higher rate than non-self-reactive T cells. Importantly, IL-23 can convert the non-pathogenic T cells into pathogenic T cells. To investigate how non-pathogenic T cells spontaneously differentiate into pathogenic T cells, we have recently generated transgenic (Tg) mice that express MS-associated human leukocyte antigen (HLA), DR2a, and myelin basic protein (MBP)-specific T cell receptor (TCR) from an MS patient. Interestingly, the MBP-specific TCR/DR2a Tg mice develop spontaneous experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and pathogenic T cells were predominantly detected in the gut lymph nodes and the large intestine as well as in the brain and spinal cord during the development of spontaneous EAE. Since IL-23 is produced in response to commensal bacteria in the gut, pathogenic T cells may develop upon exposure to IL-23 in the gut and then migrate into the brain and spinal cord. We will examine this possibility in this study.

Recent studies also indicated that commensal bacteria can not only shape intestinal immunity but also affect the development of autoimmune diseases. Interestingly, commensal bacteria can initiate the development of spontaneous autoimmune arthritis. In contrast, commensal bacteria suppress the development of autoimmune diabetes in animal models. Therefore, the effect of commensal bacteria on initiation of autoimmune disease is dependent on the type of autoimmune diseases. It is still unknown how commensal bacteria affect the initiating of spontaneous EAE. Since MBP-specific Tg T cells expand in the colon and differentiate into pathogenic T cells during the development of spontaneous EAE, we hypothesize that commensal bacteria may play an essential role in the development of pathogenic T cells in the gut and balance between pathogenic T cells-inducing and suppressor T cells-inducing commensal bacteria may control the development of pathogenic T cells in the gut. Since segmented filamentous bacteria (SFB) and Bacteroides fragilities strains promote the development of pathogenic T cells and immune-suppressor T cells, respectively, we will investigate the effect of these commensal bacteria on initiation and prevention of disease development. Although the effect of commensal bacteria on ongoing EAE has been studied, the role of commensal bacteria in the initiation and prevention of spontaneous EAE is unknown. This study will provide new insight into the effect of gut immunity on initiation and prevention of autoimmune disease against the central nervous system.