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In this report we determined interleukin 21 (<jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>21) function in <jats:styled-content style=\"fixed-case\">CLL<\/jats:styled-content> and showed that <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>21 and interleukin 4 (<jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>4) act co\u2010operatively to promote leukaemic cell proliferation without apoptosis or differentiation We further show that <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>21 increased side population (<jats:styled-content style=\"fixed-case\">SP<\/jats:styled-content>) cells, which are associated with resistance to chemotherapy and increased self\u2010renewal capacity in <jats:styled-content style=\"fixed-case\">CLL<\/jats:styled-content>. <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>21 and <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>4 are the major cytokines produced by the recently described <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>4<jats:sup>+<\/jats:sup> T follicular helper (<jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>fh) cell subset. Determination of <jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>fh cells in peripheral blood showed that patients had significantly increased numbers as compared to normal subjects although no association was found between <jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>fh numbers and <jats:italic><jats:styled-content style=\"fixed-case\">IGHV<\/jats:styled-content><\/jats:italic> gene mutational status or clinical stage. Our data suggests that the <jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>fh cytokines, <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>4 and <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>21, contribute to driving leukaemic cell proliferation in the lymph node microenvironment, and may contribute to the specific production of cells resistant to conventional chemotherapy. We suggest that increased circulating <jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>fh cells is a component of <jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>\u2010cell dysregulation in <jats:styled-content style=\"fixed-case\">CLL<\/jats:styled-content>. Our findings have implications for the therapeutic use of <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>21.<\/jats:p>","DOI":"10.1111\/bjh.12401","type":"journal-article","created":{"date-parts":[[2013,5,27]],"date-time":"2013-05-27T08:36:53Z","timestamp":1369643813000},"page":"360-370","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Enhancement of <scp>CD<\/scp>154\/<scp>IL<\/scp>4 proliferation by the <scp>T<\/scp> follicular helper (<scp>T<\/scp>fh) cytokine, <scp>IL<\/scp>21 and increased numbers of circulating cells resembling <scp>T<\/scp>fh cells in chronic lymphocytic leukaemia"],"prefix":"10.1111","volume":"162","author":[{"given":"Matthew J.","family":"Ahearne","sequence":"first","affiliation":[{"name":"Department of Cancer Studies and Molecular Medicine MRC Toxicology Unit University of Leicester Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaun","family":"Willimott","sequence":"additional","affiliation":[{"name":"Department of Cancer Studies and Molecular Medicine MRC Toxicology Unit University of Leicester Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Pi\u00f1on","sequence":"additional","affiliation":[{"name":"Department of Cancer Studies and Molecular Medicine MRC Toxicology Unit University of Leicester Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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