{"55177":{"#nid":"55177","#data":{"type":"news","title":"Study Questions Earlier Conclusions about Kinetics of T Cell Receptors","body":[{"value":"\u003Cp\u003ET cell receptors are among the most important molecules in the immune system because of their role in recognizing the antigens that signal such threats as viruses and cancer. The receptors must also distinguish these threats from the body\u2019s own cells to avoid triggering an unwanted immune system response.\u003C\/p\u003E\u003Cp\u003ERecognition requires direct physical contact between the receptor and the antigen. Researchers attempting to understand this critical mechanism, therefore, have been studying such factors as the affinity for interaction between antigens and T cell receptors, how long those interactions last and how rapidly they occur. Information about these interactions has come mostly from studying receptor molecules removed from the outer membranes of T cells \u2013 the location where they normally operate. \u003C\/p\u003E\u003Cp\u003ENow, a paper published March 31 in the journal \u003Cem\u003ENature\u003C\/em\u003E questions much of what had been believed about the kinetics of T cell receptors. Based on two techniques that mechanically study receptors as they operate on T cell membranes, the findings could lead to a reevaluation of earlier conclusions. \u003C\/p\u003E\u003Cp\u003E\u201cWe compared parameters that had been measured by using purified T cell receptor molecules to the parameters we measured from T cell receptors on the surfaces of cells, and we found dramatic differences,\u201d said Cheng Zhu, a Regents professor in the Coulter Department of Biomedical Engineering at the Georgia Institute of Technology and Emory University. \u201cWe don\u2019t yet fully understand why the T cell receptor behaves differently when it is located on the surface of a cell compared to when it is purified in solution, but this may be a warning to reconsider earlier conclusions.\u201d \u003C\/p\u003E\u003Cp\u003EThe research, done in collaboration between Georgia Tech and Emory University, was sponsored by the National Institutes of Health and the National Multiple Sclerosis Society. \u003C\/p\u003E\u003Cp\u003EIn their studies of two-dimensional receptor-antigen interactions, the researchers found as much as 8,300 times more rapid off-rates than earlier studies. More importantly, they found that the strongest interactions with antigens turned on and off the most quickly \u2013 a finding exactly opposite what had been observed in purified T cell receptors. \u003C\/p\u003E\u003Cp\u003E\u201cThe earlier conclusions state that the interaction with the most potent antigens remained stable for a long time to allow many steps of the resulting cascade to occur before dissociation,\u201d said Veronika Zarnitsyna, a research scientist in Zhu\u2019s laboratory. \u201cBut we found that the most potent antigen actually dissociated the fastest. Since mathematical models of T cell discrimination of antigens are based on these earlier conclusions, our findings may cause people to rethink what has been done.\u201d \u003C\/p\u003E\u003Cp\u003EWhen measured on the cell surfaces, the molecular interactions show an affinity range about 100 times greater and an on-rate range about 1,000 times greater than what had been reported in studies with purified T cell receptors. That is potentially important, Zhu says, because the much broader dynamic ranges found in the new research can now match the range over which the T cells respond to antigens \u2013 whereas the narrower ranges of the previous measurements could not. \u003C\/p\u003E\u003Cp\u003EZhu\u2019s research team has been studying two-dimensional molecular interactions for more than a decade, and developed a simple mechanical technique \u2013 known as the adhesion frequency assay \u2013 for assessing interactions on cell surfaces. On one micropipette, they place a T cell that they want to study. On another micropipette, they put a red blood cell on which an antigen \u2013 technically known as a peptide-major histocompatibility complex \u2013 has been placed. They then carefully move the two cells together, allowing the antigen and receptor to make contact. \u003C\/p\u003E\u003Cp\u003E\u201cWhen the molecules interact, they actually link the two cells together,\u201d Zhu explained. \u201cWe can see the interaction through the microscope if the two cells remain stuck together when we try to pull them apart.\u201d \u003C\/p\u003E\u003Cp\u003EBy measuring the elongation of the cells and the time required to create the binding, the researchers can learn about the interaction. Under computer control, the assays are repeated as many as 100 times to estimate the frequency, or the likelihood, of the interactions. \u003C\/p\u003E\u003Cp\u003E\u201cWe can measure the frequency versus the contact time,\u201d said Zhu. \u201cFrom that information, we can determine the kinetics of the interaction.\u201d \u003C\/p\u003E\u003Cp\u003EThe second technique, known as thermal fluctuation assay, detects the interactions from changes in the fluctuations due to a physical anchorage between the two surfaces. \u003C\/p\u003E\u003Cp\u003EThe researchers studied the responses of just one T cell receptor to seven different antigens. Since there are millions of different T cell receptors in the body, the researchers would like to study responses of additional receptors to see if what they found is a general principle. \u003C\/p\u003E\u003Cp\u003E\u201cNext, we plan to study a single peptide against a panel of T cell receptors to see whether the same principles apply,\u201d said Zhu. \u201cWe need to see whether or not this is a general principle governing the interaction of T cell receptors.\u201d \u003C\/p\u003E\u003Cp\u003EFor the study reported in Nature, the team used T cells provided by Lindsay Edwards, who also measured the functional T cell responses. Edwards is a student of Brian Evavold, a professor in the department of microbiology and immunology at Emory University. In addition to Zhu, Zarnitsyna, Edwards and Evavold, the paper\u2019s authors include postdoctoral scholar Baoyu Liu and two former graduate students in Zhu\u2019s lab, Jun Huang and Ning Jiang. \u003C\/p\u003E\u003Cp\u003EThe new findings could be important not only for scientists who study the immune system, but also for researchers fighting the war on cancer and companies producing vaccines. \u003C\/p\u003E\u003Cp\u003E\u201cEverything starts with the T cell receptor, and the interaction has to be a direct physical contact between the T cell and another cell in the body,\u201d Zhu noted. \u201cThis work provides a new framework for understanding how the T cell receptor function works.\u201d \u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EResearch News \u0026amp; Publications Office\u003Cbr \/\u003EGeorgia Institute of Technology\u003Cbr \/\u003E75 Fifth Street, N.W., Suite 314\u003Cbr \/\u003EAtlanta, Georgia 30308 USA\u003C\/strong\u003E \u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EMedia Relations Contacts\u003C\/strong\u003E: John Toon (404-894-6986)(\u003Ca href=\u0022mailto:jtoon@gatech.edu\u0022\u003Ejtoon@gatech.edu\u003C\/a\u003E) or Abby Vogel (404-385-3364)(\u003Ca href=\u0022mailto:avogel@gatech.edu\u0022\u003Eavogel@gatech.edu\u003C\/a\u003E). \u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EWriter\u003C\/strong\u003E: John Toon \u003C\/p\u003E","summary":null,"format":"limited_html"}],"field_subtitle":"","field_summary":[{"value":"\u003Cp\u003ET cell receptors are among the most important molecules in the immune system because of their role in recognizing the antigens that signal such threats as viruses. A paper published March 31 in the journal Nature questions much of what had been believed about the kinetics of T cell receptors.\u003C\/p\u003E","format":"limited_html"}],"field_summary_sentence":[{"value":"T cell receptors may behave differently than expected, study says."}],"uid":"27303","created_gmt":"2010-03-31 00:00:00","changed_gmt":"2016-10-08 03:05:45","author":"John Toon","boilerplate_text":"","field_publication":"","field_article_url":"","dateline":{"date":"2010-03-31T00:00:00-04:00","iso_date":"2010-03-31T00:00:00-04:00","tz":"America\/New_York"},"extras":[],"hg_media":{"55178":{"id":"55178","type":"image","title":"Cheng Zhu and researchers","body":null,"created":"1449175507","gmt_created":"2015-12-03 20:45:07","changed":"1475894489","gmt_changed":"2016-10-08 02:41:29","alt":"Cheng Zhu and researchers","file":{"fid":"190246","name":"tyb66907.jpg","image_path":"\/sites\/default\/files\/images\/tyb66907_0.jpg","image_full_path":"http:\/\/www.tlwarc.hg.gatech.edu\/\/sites\/default\/files\/images\/tyb66907_0.jpg","mime":"image\/jpeg","size":1496603,"path_740":"http:\/\/www.tlwarc.hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/tyb66907_0.jpg?itok=sG2vhte7"}},"55179":{"id":"55179","type":"image","title":"Cheng Zhu and researchers","body":null,"created":"1449175507","gmt_created":"2015-12-03 20:45:07","changed":"1475894489","gmt_changed":"2016-10-08 02:41:29","alt":"Cheng Zhu and researchers","file":{"fid":"190247","name":"tug66907.jpg","image_path":"\/sites\/default\/files\/images\/tug66907_0.jpg","image_full_path":"http:\/\/www.tlwarc.hg.gatech.edu\/\/sites\/default\/files\/images\/tug66907_0.jpg","mime":"image\/jpeg","size":1916473,"path_740":"http:\/\/www.tlwarc.hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/tug66907_0.jpg?itok=eYamHoiV"}},"55180":{"id":"55180","type":"image","title":"Studying bond formation","body":null,"created":"1449175507","gmt_created":"2015-12-03 20:45:07","changed":"1475894489","gmt_changed":"2016-10-08 02:41:29","alt":"Studying bond formation","file":{"fid":"190248","name":"tzb66907.jpg","image_path":"\/sites\/default\/files\/images\/tzb66907_0.jpg","image_full_path":"http:\/\/www.tlwarc.hg.gatech.edu\/\/sites\/default\/files\/images\/tzb66907_0.jpg","mime":"image\/jpeg","size":181537,"path_740":"http:\/\/www.tlwarc.hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/tzb66907_0.jpg?itok=jJUW2Qcv"}}},"media_ids":["55178","55179","55180"],"related_links":[{"url":"http:\/\/www.bme.gatech.edu\/","title":"Wallace H. Coulter Department of Biomedical Engineering"},{"url":"http:\/\/www.bme.gatech.edu\/facultystaff\/faculty_record.php?id=4","title":"Cheng Zhu"}],"groups":[{"id":"1188","name":"Research Horizons"}],"categories":[{"id":"146","name":"Life Sciences and Biology"},{"id":"135","name":"Research"}],"keywords":[{"id":"9049","name":"antigen"},{"id":"9048","name":"immune"},{"id":"3004","name":"receptor"},{"id":"9047","name":"T cell"}],"core_research_areas":[],"news_room_topics":[],"event_categories":[],"invited_audience":[],"affiliations":[],"classification":[],"areas_of_expertise":[],"news_and_recent_appearances":[],"phone":[],"contact":[{"value":"\u003Cp\u003E\u003Cstrong\u003EJohn Toon\u003C\/strong\u003E\u003Cbr \/\u003EResearch News \u0026amp; Publications Office\u003Cbr \/\u003E\u003Ca href=\u0022http:\/\/www.gatech.edu\/contact\/index.html?id=jt7\u0022\u003EContact John Toon\u003C\/a\u003E\u003Cbr \/\u003E\u003Cstrong\u003E404-894-6986\u003C\/strong\u003E\u003C\/p\u003E","format":"limited_html"}],"email":["jtoon@gatech.edu"],"slides":[],"orientation":[],"userdata":""}}}