T cells are strongly implicated in autoimmune diseases, as T cell immunomodulatory treatments are efficacious in reducing symptoms and there is an increased risk of developing autoimmunity by having certain alleles of the major histocompatibility complex (MHC), the antigen presenting protein for T cells. MHC alleles that increase the risk of autoimmune disease are hypothesized to poorly delete or inactivate self-reactive T cells during T cell development, allowing functional, self-reactive T cells to exist in he periphery. The process of T cell inactivation during development is called central tolerance and is a dominant mechanism in preventing autoimmunity. Currently, the functional consequences of T cell central tolerance are unknown in polyclonal mouse models of autoimmune demyelinating disease, but many groups argue that central tolerance changes the T cell populations T cell receptor (TCR) affinity for peptide-MHC (pMHC). The affinity of TCR:pMHC binding effects the proliferation and differentiation of the T cells, subsequently T cells that undergo central tolerance may differentiate differently than T cells that have not. In this grant proposal, I will investigate how the differentiation of polyclonal myelin-specific CD4 T cells is different with and without central tolerance and how CD4 T cell differentiation effects B cells contribution to a model of autoimmune demyelinating disease, experimental autoimmune encephalomyelitis (EAE). By using fluorophore tetramer enrichment and a novel micropipette adhesion frequency assay to measure the frequency and relative two-dimensional affinity (2D) of antigen-specific CD4 T cells during autoimmune demyelinating disease, we aim to demonstrate differences of T cell expansion, effector function and differentiation when central tolerance to myelin antigens is absent. In this proposal, I have outlined a strong training plan that together, with the completion of the research aims, prepares the fellowship applicant to attain the goal of becoming a research-oriented neuroimmunologist.

Public Health Relevance

This fellowship investigates the differentiation of MOG-specific T and B cells during autoimmune demyelinating disease. By understanding the cellular kinetics and differentiation of effector T and B cells during EAE, we hope to better understand how self-reactive T cell and B cells cause autoimmune demyelinating disease as well as design treatments that enhance the immune systems natural defenses against self-reactive immune cells.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Neurological Sciences Training Initial Review Group (NST)
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Utz, Ursula
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Emory University
Schools of Medicine
United States
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Barwick, Benjamin G; Scharer, Christopher D; Martinez, Ryan J et al. (2018) B cell activation and plasma cell differentiation are inhibited by de novo DNA methylation. Nat Commun 9:1900
Martinez, Ryan J; Andargachew, Rakieb; Martinez, Hunter A et al. (2016) Low-affinity CD4+ T cells are major responders in the primary immune response. Nat Commun 7:13848
Martinez, Ryan J; Morris, Anna B; Neeld, Dennis K et al. (2016) Targeted loss of SHP1 in murine thymocytes dampens TCR signaling late in selection. Eur J Immunol 46:2103-10
Martinez, Ryan J; Neeld, Dennis K; Evavold, Brian D (2015) Identification of T cell clones without the need for sequencing. J Immunol Methods 424:28-31
Martinez, Ryan J; Evavold, Brian D (2015) Lower Affinity T Cells are Critical Components and Active Participants of the Immune Response. Front Immunol 6:468