title: Enhancement of CD154/IL4 proliferation by the T follicular helper (Tfh) cytokine, IL21 and increased numbers of circulating cells resembling Tfh cells in chronic lymphocytic leukaemia.
abstract: Chronic lymphocytic leukaemia (CLL) cells encounter T-cells and proliferate in response to T-cell signals in the lymph node microenvironment. In this report we determined interleukin 21 (IL21) function in CLL and showed that IL21 and interleukin 4 (IL4) act co-operatively to promote leukaemic cell proliferation without apoptosis or differentiation We further show that IL21 increased side population (SP) cells, which are associated with resistance to chemotherapy and increased self-renewal capacity in CLL. IL21 and IL4 are the major cytokines produced by the recently described CD4(+) T follicular helper (Tfh) cell subset. Determination of Tfh cells in peripheral blood showed that patients had significantly increased numbers as compared to normal subjects although no association was found between Tfh numbers and IGHV gene mutational status or clinical stage. Our data suggests that the Tfh cytokines, IL4 and IL21, 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 Tfh cells is a component of T-cell dysregulation in CLL. Our findings have implications for the therapeutic use of IL21.
authors.affiliation: Department of Cancer Studies and Molecular Medicine, MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ahearne
authors.forename: Shaun
authors.initials: S
authors.lastname: Willimott
authors.forename: Lucia
authors.initials: L
authors.lastname: Piñon
authors.forename: D Benjamin
authors.initials: DB
authors.lastname: Kennedy
authors.forename: Fiona
authors.initials: F
authors.lastname: Miall
authors.forename: Martin J S
authors.initials: MJ
authors.lastname: Dyer
authors.forename: Simon D
authors.initials: SD
authors.lastname: Wagner
mesh_terms: D017209:Apoptosis / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology*; D005260:Female; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology; D018655:Lymphocyte Count; D008297:Male; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D016207:Cytokines; D007378:Interleukins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D023201:CD40 Ligand; D015847:Interleukin-4; D000098546:Interleukin-21
keywords: CD154; IL21; T follicular helper; chronic lymphocytic leukaemia; microenvironment