Autoimmune diseases are approaching epidemic levels, estimated to affect 5-8% of the U.S. population. Pathogenesis is attributed, in large part, to self-reactive T cells that recognize auto-antigens in affected tissues and secrete destructive, pro-inflammatory cytokines. Consequently, the differentiation of naive T cells into pro- inflammatory versus tolerogenic T helper cell lineages regulates the immunologic state of the host. T cell receptor (TCR) signals, along with local cytokines, are required for initiating T helpr cell differentiation. Understanding the precise molecular mechanisms contributing to TCR signal integration and T helper cell differentiation is important when considering immunotherapies for T cell-mediated diseases, particularly autoimmunity. We recently demonstrated that Map3k8 transduces TCR signals in naive T cells and helps to specify a Th1 transcriptional program. What is not clear is precisely how Map3k8 impinges upon the multiple TCR signaling pathways to regulate the development and functions of other T helper cell lineages. The goal of this proposal is to determine how the serine-threonine kinase Map3k8 influences TCR signaling, T helper cell differentiation, and autoimmunity. Our central hypothesis is that Map3k8 modulates TCR signal integration and thereby alters lineage commitment and effector functions of T cells in vivo.
Aim1 seeks to determine which TCR signaling pathways are defective in Map3k8-/- T cells using gene expression assays, Western blotting, and transcription factor nuclear translocation.
Aim2 will examine how Map3k8 influences T helper cell differentiation and will address the roles of specific signaling molecules and pathways in specifying T helper cell fates using in vitro T cell polarization assays and analysis of T cell populations in mice with Map3k8 ablation.
Aim3 will determine how Map3k8 contributes to T cell-mediated autoimmunity using genetically altered animal models and Map3k8 pharmacologic inhibitors. Experiments will address the underlying mechanisms of disease (or protection) by analyzing T cell migration, accumulation, and effector functions of Map3k8-/- T cells. Knowledge gained about the role of Map3k8 in TCR signaling networks will not only contribute to our fundamental understanding of normal T cell development and functions, but will also provide insight into the pathogenesis of autoimmune diseases that may ultimately elicit innovative approaches to their treatment and prevention.

Public Health Relevance

The T helper cell balance plays a critical role in maintaining immune homeostasis. The goal of this proposal is to determine how the serine-threonine kinase Map3k8 influences TCR signaling and T helper cell differentiation of inflammatory versus immunosuppressive lineages. Understanding this process will shed light on T cell-mediated disease pathogenesis and may ultimately provide novel means for treating human infectious and autoimmune diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Rothermel, Annette L
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University of Georgia
Schools of Veterinary Medicine
United States
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