An important recently recognized barrier to induction of immunologic tolerance in humans is the fact that the adaptive immune response, by virtue of evolutionary design, is destined to generate immunologic memory;and initial data suggest that memory T cells tend to be resistant to induction of tolerance. EAE is an inflammatory disease of the central nervous system that mimics certain aspects of MS. We have established a new model of EAE that is mediated by antigen-specific memory T cells that is distinct from disease mediated by effector T cells. The major goal of this project is to investigate the role of memory T cells EAE, and to investigate their susceptibility to tolerance strategies in vivo.
Aim1 : We will investigate the characteristics of disease mediated by memory versus effector T cells, including clinical features, central nervous system (CNS) pathology, and peripheral immune responses.
Aim 2 : Our hypothesis is that autoreactive memory T cells can be activated by nonspecific immune stimuli (viral infection, inflammation, vaccination) leading to reactivation/progression of clinical disease. In this aim we will investigate which stimuli can activate autoreactive memory T cells in vivo and define the clinical and pathological disease pattern mediated by these cells and the mechanisms of how this happens.
Aim 3 : Our hypothesis is that autoreactive memory T cells are less dependent on conventional (CD28) T cell costimulatory pathways for activation and require distinct and unique T cell costimulatory signals for full activation, differentiation and survival in vivo. These cosimulatory pathways include ICOS-B7h and CD134-CD143L. Using blocking antibodies against B7h and CD134L, we will investigate the functions and mechanisms of these pathways in regulating autoimmune disease mediated by memory T cells in vivo.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-Y (04))
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Esch, Thomas R
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Brigham and Women's Hospital
United States
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Zhu, Bing; Buttrick, Thomas; Bassil, Ribal et al. (2013) IL-4 and retinoic acid synergistically induce regulatory dendritic cells expressing Aldh1a2. J Immunol 191:3139-51
Purwar, Rahul; Schlapbach, Christoph; Xiao, Sheng et al. (2012) Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat Med 18:1248-53
Okada, Hideho; Khoury, Samia J (2012) Type17 T-cells in central nervous system autoimmunity and tumors. J Clin Immunol 32:802-8
Elyaman, Wassim; Bassil, Ribal; Bradshaw, Elizabeth M et al. (2012) Notch receptors and Smad3 signaling cooperate in the induction of interleukin-9-producing T cells. Immunity 36:623-34
Zhu, Bing; Trikudanathan, Subbulaxmi; Zozulya, Alla L et al. (2012) Immune modulation by Lacto-N-fucopentaose III in experimental autoimmune encephalomyelitis. Clin Immunol 142:351-61
Bassil, Ribal; Zhu, Bing; Lahoud, Youmna et al. (2011) Notch ligand delta-like 4 blockade alleviates experimental autoimmune encephalomyelitis by promoting regulatory T cell development. J Immunol 187:2322-8
Zhu, Bing; Kennedy, Jennifer K; Wang, Yue et al. (2011) Plasticity of Ly-6C(hi) myeloid cells in T cell regulation. J Immunol 187:2418-32
Elyaman, Wassim; Bradshaw, Elizabeth M; Uyttenhove, Catherine et al. (2009) IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci U S A 106:12885-90
Elyaman, Wassim; Kivisakk, Pia; Reddy, Jay et al. (2008) Distinct functions of autoreactive memory and effector CD4+ T cells in experimental autoimmune encephalomyelitis. Am J Pathol 173:411-22