Experimental autoimmune encephalomyelitis (EAE) is a T cell mediated autoimmune disease that serves as an animal model of Multiple Sclerosis (MS). We have previously generated a MOG TcR (2D2) transgenic mouse which, when crossed onto a MOG B cell knock-in TH mouse, develop an accelerated, severe disease with inflammatory lesions distributed preferentially in the optic nerve and spinal cord, typical of neuromyelitis optica or Devic's disease observed in human MS. The mechanisms by which autopathogenic T and B cells collaborate to induce such severe disease in the 2D2 x TH mice are not known. Signaling via the B7:CD28/CTLA4 costimulatory pathway can provide a potent costimulatory signal for T and B cell activation, but other pathways like ICOS:ICOSL and TIM-1:Tim-1L pathways also play important roles in CD4+ T cell activation, differentiation, and effector function. The overall goal of this project is to define the role of these 3 different costimulatory pathways, B7:CD28/CTLA4, ICOS-ICOSL and Tim-1:Tim1L pathway in the activation of pathogenic T and B cells in the development of Devic's disease in 2D2 x TH mice. Our hypothesis is that, whereas the B7:CD28/CTLA4 pathway plays a crucial role in the induction and effector functions of the autopathogenic T cells, ICOS and TIM-1 pathways also play important roles in T:B cell collaboration and generation of pathogenic effector T and B cells. The 2D2 x TH mice that develop spontaneous Devic's disease provide us a unique opportunity to study the role of costimulatory pathways in the generation of Devic's disease. To address these issues, we have proposed the following specific aims: 1: Characterize the MOG TcR and MOG B cell """"""""knock-in"""""""" mice for their ability to induce clinical Devic's-like disease and T:B cell collaboration. Since the mice develop spontaneous disease, we will determine when and where the T and B cells are activated, what is the role of B cells in antigen presentation and what is the molecular basis for the induction of Devic's disease;2: Compare the roles of the CD28 and ICOS costimulatory pathways in the generation of pathogenic B and T cells and induction of Devic's like disease in the 2D2xTH mice. We will examine the role of B7-1/B7-2 and ICOSL in the activation of B cells as APCs and generation of T cell dependent antibody production, and test their effect on the induction of Devic's disease when crossed to the 2D2 x TH mice;3: Study the relationships among the CD28, ICOS and TIM-1 costimulatory pathways in the induction and effector phases of EAE. We will test the effect of loss of ICOS and CD28 on the expression of Tim-1, test whether anti-Tim-1 antibody preferentially generates pathogenic effector T cells and inhibits functions of regulatory T cells, and whether loss of Tim-1 will inhibit Devic's disease in the 2D2 x TH mice when bred with Tim-1-/- mice. Taken together, these studies should provide clear answers, enabling us to define mechanisms by which these costimulatory pathways influence the development pathogenic T and B cell effectors and in regulating T:B cell collaboration and development of Devic's disease. Project Narrative: The overall goal of this project is to study the roles of the costimulatory pathways (B7:CD28/CTLA4, ICOS:ICOSL and TIM-1:TIM-1L) in T:B collaboration and in inducing autopathogenic T and B cell responses. This will be undertaken by using MOG TcR transgenic mice that co-express MOG specific B cell receptors and develop fulminant autoimmunity of the CNS spontaneously similar to human Devic's disease. The effect of each of the three costimulatory pathways on the development of the disease will be analyzed.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Joller, Nicole; Lozano, Ester; Burkett, Patrick R et al. (2014) Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 40:569-81
Xiao, Sheng; Brooks, Craig R; Zhu, Chen et al. (2012) Defect in regulatory B-cell function and development of systemic autoimmunity in T-cell Ig mucin 1 (Tim-1) mucin domain-mutant mice. Proc Natl Acad Sci U S A 109:12105-10
Peters, Anneli; Lee, Youjin; Kuchroo, Vijay K (2011) The many faces of Th17 cells. Curr Opin Immunol 23:702-6
Peters, Anneli; Pitcher, Lisa A; Sullivan, Jenna M et al. (2011) Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity 35:986-96
Xiao, Sheng; Zhu, Bing; Jin, Hulin et al. (2011) Tim-1 stimulation of dendritic cells regulates the balance between effector and regulatory T cells. Eur J Immunol 41:1539-49
Joller, Nicole; Hafler, Jason P; Brynedal, Boel et al. (2011) Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol 186:1338-42
Riol-Blanco, Lorena; Lazarevic, Vanja; Awasthi, Amit et al. (2010) IL-23 receptor regulates unconventional IL-17-producing T cells that control bacterial infections. J Immunol 184:1710-20
Mitsdoerffer, Meike; Lee, Youjin; Jager, Anneli et al. (2010) Proinflammatory T helper type 17 cells are effective B-cell helpers. Proc Natl Acad Sci U S A 107:14292-7
Rodriguez-Manzanet, Roselynn; Sanjuan, Miguel A; Wu, Henry Y et al. (2010) T and B cell hyperactivity and autoimmunity associated with niche-specific defects in apoptotic body clearance in TIM-4-deficient mice. Proc Natl Acad Sci U S A 107:8706-11
Jager, A; Kuchroo, V K (2010) Effector and regulatory T-cell subsets in autoimmunity and tissue inflammation. Scand J Immunol 72:173-84

Showing the most recent 10 out of 52 publications