New Regulators of Immune System Discovered

By creating a new method of discovering targets involved in signaling pathways, researchers have uncovered novel modulators of T-cell receptor signaling, which could aid in the development of drugs to target the immune response. The findings were reported in the September 15, 2003, issue of the Journal of Biology, published by BioMed Central, an online Internet publisher.

The researchers conducted a functional genome-wide screen, using retroviruses to carry lymphoid genes into cells. These were lymphoid genes that regulate T-cell receptor signaling when expressed. Normally, when T-cell receptors are activated, a cell surface marker called CD69 is up-regulated. However, cells were selected that failed to up-regulate this protein when given a new gene to express. The researchers confirmed that this repression was caused by the introduced gene and was not a side effect of the procedure. After three rounds of selection, 33 individual genes were cloned. Some were known to have a role in the immune response, some had unrelated functions, and some were completely novel. Experiments on three of the genes (EDG1, PAK2, and TRAC-1) confirmed they were normally expressed in the lymphoid system and that truncated versions could repress T-cell receptor signaling.

Until now, the identification of novel components in these pathways has been slow and time consuming, according to the team of scientists at Rigel Pharmaceuticals (South San Francisco, CA, USA) who conducted the research, led by Dr. Charlene Liao, as part of a collaboration with Novartis (London, UK).

"This approach provides a tool for functional cloning of regulators in numerous signal transduction pathways,” write the authors. "Importantly, the outlined strategy, which requires no prior sequence information of the players involved, does not bias the search to previously known signaling molecules, molecules flagged by DNA-array technologies, or signaling molecules discovered in other contexts.”





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