Normally activation of naive T cells requires two signals. 1. A signal through the T cell receptor (TCR) which provides antigen specificity to the response. 2. Signals through co-stimulatory molecules, which are necessary for proliferation, survival and cytokine production. In the absence of co-stimulatory signals T cells are not effectively activated, and may even be rendered anergic or more ..
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Description:
Normally activation of naive T cells requires two signals. 1. A signal through the T cell receptor (TCR) which provides antigen specificity to the response. 2. Signals through co-stimulatory molecules, which are necessary for proliferation, survival and cytokine production. In the absence of co-stimulatory signals T cells are not effectively activated, and may even be rendered anergic or unresponsive to subsequent signaling. This lack of costimulation has been shown in multiple model systems to be a major factor in the limited strength and effectiveness of anti-tumor T cell responses. The goal of this project is to identify small molecule compounds that will stimulate T cell activation in the presence of TCR signaling but in the absence of co-stimulatory signals, thereby allowing activation of naive T cells in the absence of co-stimulation. Identification of such compounds would have clear experimental and clinical applications in instances where desirable antigen-specific immune responses are not generated due to a lack of co-stimulation, for example in the generation of anti-tumor responses.
In collaboration between the National Cancer Institute and NIH Chemical Genomics Center, a high-throughput amenable screen was developed to discover small molecules that co-stimulate and activate human T cell receptors. The screen was carried out using a novel homogeneous time resolved fluorescence energy transfer (HTRF) assay to measure production of the cytokine IL-2 by activated T cells and were tested against the NIH Molecular Libraries Small Molecule Repository (MLSMR). Secondary assays have also been developed to further test compounds of interest. Please see linked AID for more details.
NIH Chemical Genomics Center [NCGC]
NIH Molecular Libraries Probe Centers Network [MLPCN]
MLPCN Grant: MH090820-01
Assay Submitter (PI): Richard Hodes, National Cancer Institute, NIH
In collaboration between the National Cancer Institute and NIH Chemical Genomics Center, a high-throughput amenable screen was developed to discover small molecules that co-stimulate and activate human T cell receptors. The screen was carried out using a novel homogeneous time resolved fluorescence energy transfer (HTRF) assay to measure production of the cytokine IL-2 by activated T cells and were tested against the NIH Molecular Libraries Small Molecule Repository (MLSMR). Secondary assays have also been developed to further test compounds of interest. Please see linked AID for more details.
NIH Chemical Genomics Center [NCGC]
NIH Molecular Libraries Probe Centers Network [MLPCN]
MLPCN Grant: MH090820-01
Assay Submitter (PI): Richard Hodes, National Cancer Institute, NIH
Protocol
Please see linked AIDs for a specific detailed protocol for each assay.
Comment
This project is on-going and will be updated at a later point with findings.
Additional Information
Grant Number: MH090820
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