T lymphocyte (T cell) activation plays a critical role in immune responses. Deregulation of T cell activation will result in cancer, autoimmune, or immunodeficiency diseases. T cell activation is induced by major-histocompatibility-complex (MHC) molecules on antigen-presenting cells (APC) presenting antigen peptides to T cell receptors (TCR) on the surface of T cells. This stimulation on TCR/CD3 complexes induces a series of signal transduction cascades leading to activation of various kinases such IKK, JNK, and p38. These activated kinases further regulate the activation of multiple transcription factors including NF-?B, NF-AT, and AP-1. These transcription factors ultimately control the gene expression profile in T cells, leading to production of cytokines, and T cell proliferation and differentiation. Recent studies from our lab and others demonstrate that CARMA1, a scaffold molecule, plays a critical role in NF-?B and JNK activation following the stimulation of TCR. Although it is clear that CARMA1 mediates TCR-induced NF-?B activation through regulating I?B kinase (IKK) complex, the molecular mechanism by which CARMA1 is involved in IKK activation is not fully defined. In addition, the role of CARMA1-mediated JNK activation in T cell activation and differentiation remains to be determined. To investigate how CARMA1 is involved in TCR-induced signal transduction and its role in T cell proliferation and differentiation, four specific aims are proposed in this application.
The specific aims are: (1) to determine how CARMA1 is recruited into immunological synapse;(2) to determine the signaling pathways mediating TCR-induced IKK activation;(3) to define the role of CARMA1-mediated JNK2 activation in T cell activation and differentiation. These studies will not only reveal the basic mechanism of the TCR-induced signaling pathway, but also provide the molecular insight for determining the unknown causes of autoimmunity, immunodeficiency, and T cell malignancy. Therefore, the results from these studies will provide the molecular basis for designing novel therapeutic agents to treat these diseases. Public Health Relevance Statement: T cell activation and differentiation plays a critical role in immune responses. In this application, we propose to investigate the role of CARMA1 and its associated signaling events in T cell receptor-induced NF-?B and JNK activation that plays pivotal roles for T cell activation and differentiation. The results from these studies will provide the molecular basis for designing novel therapeutic agents to treat autoimmunity, immunodeficiency, leukemia, and lymphoma.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Cellular and Molecular Immunology - A Study Section (CMIA)
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Marino, Pamela
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University of Texas MD Anderson Cancer Center
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