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To determine whether TCR down\u2010regulation affects the cytotoxicity of Tc cells, we studied TCR down\u2010regulation\u2010deficient CD3\u03b3LLAA mice. We found that Tc cells from CD3\u03b3LLAA mice have reduced cytotoxicity due to a specific deficiency in exocytosis of lytic granules. To determine whether this defect was reflected in an increased susceptibility to virus infections, we studied the course of ectromelia virus (ECTV) infection. We found that the susceptibility to ECTV infection was significantly increased in CD3\u03b3LLAA mice with a mortality rate almost as high as in granzyme B knock\u2010out mice. Finally, we found that TCR signaling in CD3\u03b3LLAA Tc cells caused highly increased tyrosine phosphorylation and activation of the c\u2010Cbl ubiquitin ligase, and that the impaired exocytosis of lytic granules could be rescued by the knockdown of c\u2010Cbl. Thus, our work demonstrates that TCR down\u2010regulation critically increases Tc cell cytotoxicity and protection against poxvirus infection.<\/jats:p>","DOI":"10.1002\/eji.201141413","type":"journal-article","created":{"date-parts":[[2011,5,17]],"date-time":"2011-05-17T11:05:19Z","timestamp":1305630319000},"page":"1948-1957","source":"Crossref","is-referenced-by-count":8,"title":["TCR down\u2010regulation boosts T\u2010cell\u2010mediated cytotoxicity and protection against poxvirus infections"],"prefix":"10.1002","volume":"41","author":[{"given":"Ann K.","family":"Hansen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Regner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlotte M.","family":"Bonefeld","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lasse","family":"Boding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Kongsbak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niels","family":"\u00d8dum","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arno","family":"M\u00fcllbacher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carsten","family":"Geisler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina R.","family":"von Essen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2011,5,27]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.25.022106.141548"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri819"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.111.6.2327"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.173.5.1099"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.133.5.2762"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.23.090506.123521"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05071"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.f.215"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri911"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/4779"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.4.2339"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00237-9"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.1.145"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.08.024"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.09.004"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200939341"},{"key":"e_1_2_6_18_2","doi-asserted-by":"crossref","first-page":"260","DOI":"10.4049\/jimmunol.161.1.260","article-title":"Two distinct pathways exist for down\u2010regulation of the TCR","volume":"161","author":"Lauritsen J. 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