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T cells rely on 'rheostat' to help ensure that the immune response matches the threat
Date:4/30/2013

necting the T cell receptor to the cell's signaling pathways. Unlike other immune cell types whose receptors have just one or two ITAMs, T cell receptors have 10 ITAMs.

This study suggests that having so many ITAMs gives T cells greater flexibility in responding to threats. The research was published online February 3. Earlier work from Vignali's laboratory showed that mice whose T cells had as few as two working ITAMs could produce cytokines, molecules that combat infection by fueling inflammation. Those T cells, however, could not proliferate.

This study helps to explain why. The new study showed that without a full complement of ITAMs, T cell receptors did not assemble the machinery needed to launch proliferation. That meant proteins named Notch1 and Vav1 did not interact and connect to the T cell receptor. The study showed that these interactions were required to turn on production of another protein, c-Myc, which in turn drives proliferation.

Previous research from the laboratory of Douglas Green, Ph.D., chair of the St. Jude Department of Immunology, showed c-Myc plays a key role in preparing T cells for rapid proliferation. Until this study, however, the steps involved in inducing c-Myc production were unknown.

"Our study shows that Notch1 activation is required for maximal T cell proliferation," Vignali said. The study identified the importance of Notch1 and its association with the T cell receptor, via Vav1, in T cell proliferation. The researchers also showed that fewer functional T cell receptor ITAMs meant less Notch1 was activated.

The perceived strength of the T cell receptor signaling response also affected c-Myc expression in T cells but not cytokine secretion. T cells gauge their response in part by how strongly an antigen binds to the T cell receptor. Antigens are the pieces of the virus or other invader that alert T cells to a problem. A strong bond triggers higher levels of c-Myc and more proliferatio
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Contact: Summer Freeman
summer.freeman@stjude.org
901-595-3061
St. Jude Children's Research Hospital
Source:Eurekalert

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