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Most efforts to improve the CD8<jats:sup>+<\/jats:sup> T cell immunogenicity of these vaccines have focused on co\u2010administration of adjuvant to support cross\u2010presentation and dendritic cell maturation. In addition, it has been shown that CD4<jats:sup>+<\/jats:sup> T cell help during the priming phase contributes to the generation of protective CD8<jats:sup>+<\/jats:sup> memory T cells. In this report we demonstrate that the depletion of CD4<jats:sup>+<\/jats:sup> T cells paradoxically enhances long\u2010lasting CD8\u2010mediated protective immunity upon protein vaccination. Functional and genetic <jats:italic>in vivo<\/jats:italic> inactivation experiments attribute this enhancement primarily to MHC class\u2004II\u2010restricted CD4<jats:sup>+<\/jats:sup> regulatory T cells (Treg), which appear to physiologically suppress the differentiation process towards long\u2010living effector memory T cells. Since, in functional terms, this suppression by Treg largely exceeds the positive effects of conventional CD4<jats:sup>+<\/jats:sup> T cell help, even the absence of all CD4<jats:sup>+<\/jats:sup> T cells or lack of MHC class\u2004II\u2010mediated interactions on priming dendritic cells result in enhanced CD8<jats:sup>+<\/jats:sup> T cell immunogenicity. These findings have important implications for the improvement of vaccines against intracellular pathogens or tumors, especially in patients with highly active Treg.<\/jats:p><jats:p>Supporting Information for this article is available at www.wiley\u2010vch.de\/contents\/jc_2040\/2008\/37966_s.pdf<\/jats:p>","DOI":"10.1002\/eji.200737966","type":"journal-article","created":{"date-parts":[[2008,5,8]],"date-time":"2008-05-08T15:34:00Z","timestamp":1210260840000},"page":"1585-1597","source":"Crossref","is-referenced-by-count":22,"title":["Circumvention of regulatory CD4<sup>+<\/sup> T cell activity during cross\u2010priming strongly enhances T cell\u2010mediated immunity"],"prefix":"10.1002","volume":"38","author":[{"given":"Antje","family":"Heit","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Friedemann","family":"Gebhardt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharina","family":"Lahl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Neuenhahn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Schmitz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florian","family":"Anderl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hermann","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim","family":"Sparwasser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk\u2004H.","family":"Busch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathrin","family":"Kastenm\u00fcller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2008,5,20]]},"reference":[{"key":"e_1_2_8_1_2","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2859-5-23"},{"key":"e_1_2_8_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.21.120601.141126"},{"key":"e_1_2_8_3_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.20.083001.084359"},{"key":"e_1_2_8_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.24.021605.090552"},{"key":"e_1_2_8_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni712"},{"key":"e_1_2_8_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/35047123"},{"key":"e_1_2_8_7_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.20.100301.064842"},{"key":"e_1_2_8_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.copbio.2004.09.006"},{"key":"e_1_2_8_9_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.7.4373"},{"key":"e_1_2_8_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni0406-363"},{"key":"e_1_2_8_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1136080"},{"key":"e_1_2_8_12_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.4.2244"},{"key":"e_1_2_8_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/30996"},{"key":"e_1_2_8_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/30989"},{"key":"e_1_2_8_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/31002"},{"key":"e_1_2_8_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01441"},{"key":"e_1_2_8_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1082305"},{"key":"e_1_2_8_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1083317"},{"key":"e_1_2_8_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0308054101"},{"key":"e_1_2_8_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04790"},{"key":"e_1_2_8_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri1461"},{"key":"e_1_2_8_22_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.164.1.363"},{"key":"e_1_2_8_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2006.05.008"},{"key":"e_1_2_8_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80540-3"},{"key":"e_1_2_8_25_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.21.120601.141122"},{"key":"e_1_2_8_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1437"},{"key":"e_1_2_8_27_2","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.4049\/jimmunol.155.3.1151","article-title":"Immunologic self\u2010tolerance maintained by activated T cells expressing IL\u20102 receptor alpha\u2010chains (CD25). 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