title: Abnormally differentiated CD4+ or CD8+ T cells with phenotypic and genetic features of double negative T cells in human Fas deficiency.
abstract: Accumulation of CD3(+) T-cell receptor (TCR)αβ(+)CD4(-)CD8(-) double-negative T cells (DNT) is a hallmark of autoimmune lymphoproliferative syndrome (ALPS). DNT origin and differentiation pathways remain controversial. Here we show that human ALPS DNT have features of terminally differentiated effector memory T cells reexpressing CD45RA(+) (TEMRA), but are CD27(+)CD28(+)KLRG1(-) and do not express the transcription factor T-bet. This unique phenotype was also detected among CD4(+) or CD8(+) ALPS TEMRA cells. T-cell receptor β deep sequencing revealed a significant fraction of shared CDR3 sequences between ALPS DNT and both CD4(+) and CD8(+)TEMRA cells. Moreover, in ALPS patients with a germ line FAS mutation and somatic loss of heterozygosity, in whom biallelic mutant cells can be tracked by absent Fas expression, Fas-negative T cells accumulated not only among DNT, but also among CD4(+) and CD8(+)TEMRA cells. These data indicate that in human Fas deficiency DNT cannot only derive from CD8(+), but also from CD4(+) T cells. Furthermore, defective Fas signaling leads to aberrant transcriptional programs and differentiation of subsets of CD4(+) and CD8(+) T cells. Accumulation of these cells before their double-negative state appears to be an important early event in the pathogenesis of lymphoproliferation in ALPS patients.
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany;
authors.forename: Anne
authors.initials: A
authors.lastname: Rensing-Ehl
authors.affiliation: Department of Internal Medicine 5, Haematology and Oncology, University Hospital Erlangen, Erlangen, Germany;
authors.forename: Simon
authors.initials: S
authors.lastname: Völkl
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany; Center for Paediatrics and Adolescent Medicine, University Medical Center, University of Freiburg, Freiburg, Germany;
authors.forename: Carsten
authors.initials: C
authors.lastname: Speckmann
authors.affiliation: Institute for Transfusion Medicine, University of Ulm, Ulm, Germany;
authors.forename: Myriam Ricarda
authors.initials: MR
authors.lastname: Lorenz
authors.affiliation: Institute of Pathology, Charité - University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany;
authors.forename: Julia
authors.initials: J
authors.lastname: Ritter
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany; Center for Paediatrics and Adolescent Medicine, University Medical Center, University of Freiburg, Freiburg, Germany;
authors.forename: Ales
authors.initials: A
authors.lastname: Janda
authors.affiliation: Department of Paediatric Immunology, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom; Institute of Cellular Immunology, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Mario
authors.initials: M
authors.lastname: Abinun
authors.affiliation: Institute of Immunology, Department of Medicine Microbiology and Hygiene, and.
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Pircher
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany; Department of Internal Medicine II, University Medical Center Freiburg, Freiburg, Germany;
authors.forename: Bertram
authors.initials: B
authors.lastname: Bengsch
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany; Department of Internal Medicine II, University Medical Center Freiburg, Freiburg, Germany;
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany;
authors.forename: Ilka
authors.initials: I
authors.lastname: Fuchs
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany;
authors.forename: Sandra
authors.initials: S
authors.lastname: Ammann
authors.affiliation: Department of Internal Medicine 5, Haematology and Oncology, University Hospital Erlangen, Erlangen, Germany;
authors.forename: Andrea
authors.initials: A
authors.lastname: Allgäuer
authors.affiliation: Department of Paediatrics, Jena University Hospital, Jena, Germany;
authors.forename: Karim
authors.initials: K
authors.lastname: Kentouche
authors.affiliation: Department of Paediatric Immunology, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom; Institute of Cellular Immunology, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Andrew
authors.initials: A
authors.lastname: Cant
authors.affiliation: Department of Paediatric Immunology, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom; Institute of Cellular Immunology, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Sophie
authors.initials: S
authors.lastname: Hambleton
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hanover Hannover, Germany;
authors.forename: Claudia
authors.initials: C
authors.lastname: Bettoni da Cunha
authors.affiliation: Division of Pediatric Haematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Göttingen, Göttingen, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Huetker
authors.affiliation: Division of Pediatric Haematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Göttingen, Göttingen, Germany;
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kühnle
authors.affiliation: Department of Paediatric Haematology/Oncology, University Medical Center Bremen, Bremen, Germany.
authors.forename: Arnulf
authors.initials: A
authors.lastname: Pekrun
authors.affiliation: Paediatric Haematology-Oncology, Medical University of Graz, Graz, Austria; and.
authors.forename: Markus G
authors.initials: MG
authors.lastname: Seidel
authors.affiliation: Institute of Pathology, Charité - University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Hummel
authors.affiliation: Department of Internal Medicine 5, Haematology and Oncology, University Hospital Erlangen, Erlangen, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Mackensen
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany; Institute for Transfusion Medicine, University of Ulm, Ulm, Germany; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service, Ulm, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany; Center for Paediatrics and Adolescent Medicine, University Medical Center, University of Freiburg, Freiburg, Germany;
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
mesh_terms: D000293:Adolescent; D000328:Adult; D056735:Autoimmune Lymphoproliferative Syndrome / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D056726:Genetic Association Studies; D018095:Germ-Line Mutation; D006801:Humans; D007156:Immunologic Memory; D017493:Leukocyte Common Antigens / Q000378:metabolism; D019656:Loss of Heterozygosity; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D055815:Young Adult; D019014:fas Receptor / Q000172:deficiency* / Q000235:genetics*; D000098815:T-bet Transcription Factor
chemical_list: C491901:FAS protein, human; D016693:Receptors, Antigen, T-Cell, alpha-beta; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D019014:fas Receptor; D017493:Leukocyte Common Antigens