Antigen-stimulated T cell division and acquisition of effector functions are dependent upon signal transduction directed by the T cell receptor (TCR), and the consequent activation of a number of transcription factors that effect changes in gene expression. Transcription factors of the NF-KB family are of central importance in this process. The TCR-regulated NF-KB activation pathway will be investigated through a combination of molecular, biochemical, and highly advanced imaging techniques. The goal is to establish mechanistic relationships between 1) protein-protein interactions, 2) subcellular protein organization and 3) biochemical modification of cytoplasmic signal transducers in the TCR-directed NF-KB pathway. This goal will be accomplished via the execution of three specific aims:
Aim1. Todetermine the mechanistic significance of localizedprotein-protein associations of signaling intermediates in TCR-directed activation of NF-KB. We will test the hypothesis that TCR-directed NF-KB signaling involves the orchestrated assembly and disassembly of defined protein complexes into discrete subcellular domains, with specific protein complexes playing a critical mechanistic role.
Aim 2. Toinvestigate, in individual cells, the mechanistic relationship between antigen signal strength, assembly of signal transduction complexes, and successful activation of the TCR-directed NF-KB signal transduction pathway. Experiments will be directed towards the evaluation of the hypothesis that antigen signals through the TCR are converted into """"""""binary"""""""" outcomes of either no activation or full activation of effector functions. Furthermore, these functional outcomes are dependent on signal transduction decision events made at the single-cell level.
Aim 3. To define the roles of phosphorylation and the MALT1 interaction domain in the TCR- mediated degradation and activation ofBcHO. We will perform experiments to test the hypothesis that activation and proteolytic destruction of BcHO are mechanistically coupled, and that both processes are regulated by BcHO interaction with MALT1 and by PKC-dependent phosphorylation of BcHO. These studies will help establish the basic research foundation that could lead to the development of novel immuno-modulatory drugs, which would function via highly specfic inhibition of antigen-receptor mediated activation of the NF-KB signaling cascade.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI057481-05
Application #
7758850
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Mallia, Conrad M
Project Start
2006-02-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2012-01-31
Support Year
5
Fiscal Year
2010
Total Cost
$321,454
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Bethesda
State
MD
Country
United States
Zip Code
20817
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Paul, Suman; Kashyap, Anuj K; Jia, Wei et al. (2012) Selective autophagy of the adaptor protein Bcl10 modulates T cell receptor activation of NF-?B. Immunity 36:947-58
Paul, Suman; Schaefer, Brian C (2012) Selective autophagy regulates T cell activation. Autophagy 8:1690-2
Cartwright, Natalia G; Kashyap, Anuj K; Schaefer, Brian C (2011) An active kinase domain is required for retention of PKC? at the T cell immunological synapse. Mol Biol Cell 22:3491-7
Kingeter, Lara M; Schaefer, Brian C (2010) Malt1 and cIAP2-Malt1 as effectors of NF-kappaB activation: kissing cousins or distant relatives? Cell Signal 22:9-22
Kingeter, Lara M; Paul, Suman; Maynard, Sean K et al. (2010) Cutting edge: TCR ligation triggers digital activation of NF-kappaB. J Immunol 185:4520-4
Lamb, Erika W; Walls, Colleen D; Pesce, John T et al. (2010) Blood fluke exploitation of non-cognate CD4+ T cell help to facilitate parasite development. PLoS Pathog 6:e1000892
Kingeter, Lara M; Schaefer, Brian C (2009) Expanding the multicolor capabilities of basic confocal microscopes by employing red and near-infrared quantum dot conjugates. BMC Biotechnol 9:49
Langel, Felicia D; Jain, Nidhi A; Rossman, Jeremy S et al. (2008) Multiple protein domains mediate interaction between Bcl10 and MALT1. J Biol Chem 283:32419-31
Kingeter, Lara M; Schaefer, Brian C (2008) Loss of protein kinase C theta, Bcl10, or Malt1 selectively impairs proliferation and NF-kappa B activation in the CD4+ T cell subset. J Immunol 181:6244-54