title: Abnormalities of follicular helper T-cell number and function in Wiskott-Aldrich syndrome.
abstract: Wiskott-Aldrich syndrome protein (WASp) is a hematopoietic-specific regulator of actin nucleation. Wiskott-Aldrich syndrome (WAS) patients show immunodeficiencies, most of which have been attributed to defective T-cell functions. T follicular helper (Tfh) cells are the major CD4(+) T-cell subset with specialized B-cell helper capabilities. Aberrant Tfh cells activities are involved in immunopathologies such as autoimmunity, immunodeficiencies, and lymphomas. We found that in WAS patients, the number of circulating Tfh cells was significantly reduced due to reduced proliferation and increased apoptosis, and Tfh cells were Th2 and Th17 polarized. The expression of inducible costimulator (ICOS) in circulating Tfh cells was higher in WAS patients than in controls. BCL6 expression was decreased in total CD4(+) T and Tfh cells of WAS patients. Mirroring the results in patients, the frequency of Tfh cells in WAS knockout (KO) mice was decreased, as was the frequency of BCL6(+) Tfh cells, but the frequency of ICOS(+) Tfh cells was increased. Using WAS chimera mice, we found that the number of ICOS(+) Tfh cells was decreased in WAS chimera mice, indicating that the increase in ICOS(+) Tfh cells in WAS KO mice was cell extrinsic. The data from in vivo CD4(+) naive T-cell adoptive transfer mice as well as in vitro coculture of naive B and Tfh cells showed that the defective function of WASp-deficient Tfh cells was T-cell intrinsic. Consistent findings in both WAS patients and WAS KO mice suggested an essential role for WASp in the development and memory response of Tfh cells and that WASp deficiency causes a deficient differentiation defect in Tfh cells by downregulating the transcription level of BCL6.
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, and.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, and.
authors.forename: Rongxin
authors.initials: R
authors.lastname: Dai
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, and.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Li
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, and.
authors.forename: Hongyi
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, and.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, and.
authors.forename: Lina
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, and.
authors.forename: Hongqiang
authors.initials: H
authors.lastname: Du
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, and.
authors.forename: Guangjin
authors.initials: G
authors.lastname: Luo
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, and Division of Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China; and.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Wu
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, and.
authors.forename: Linlin
authors.initials: L
authors.lastname: Niu
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, and Division of Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China; and.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: An
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, and Division of Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China; and.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, and Division of Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China; and.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD.
authors.forename: Wenxia
authors.initials: W
authors.lastname: Song
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, and.
authors.forename: Chaohong
authors.initials: C
authors.lastname: Liu
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, and Division of Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China; and.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001402:B-Lymphocytes; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology / Q000502:physiology; D016022:Case-Control Studies; D002454:Cell Differentiation; D002478:Cells, Cultured; D018858:Germinal Center / Q000276:immunology / Q000473:pathology*; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000074462:Positive Regulatory Domain I-Binding Factor 1; D054380:Receptors, CXCR5 / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000473:pathology* / Q000502:physiology*; D014923:Wiskott-Aldrich Syndrome / Q000097:blood / Q000276:immunology* / Q000473:pathology; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics; D000098546:Interleukin-21
chemical_list: C095085:CXCR5 protein, human; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D007378:Interleukins; D054380:Receptors, CXCR5; D012097:Repressor Proteins; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1; D000098546:Interleukin-21