title: The composition and differentiation potential of the duodenal intraepithelial innate lymphocyte compartment is altered in coeliac disease.
abstract: Coeliac disease (CD), a gluten-induced enteropathy, alters the composition and function of duodenal intraepithelial T cells. The intestine also harbours four types of CD3-negative intraepithelial lymphocytes (IELs) with largely unknown function: CD56(-)CD127(-), CD56(-)CD127(+), CD56(+)CD127(-) and CD56(+)CD127(+). Here we aimed to gain insight into the potential function of these innate IELs in health and disease.
  
  
  
  We determined the phenotypes, relative abundance and differentiation potential of these innate IEL subsets in duodenal biopsies from controls and patients with CD or patients with refractory CD type II (RCDII).
  
  
  
  Hierarchical clustering analysis of the expression of 15 natural killer and T cell surface markers showed that innate IELs differed markedly from innate peripheral blood lymphocytes and divided innate IEL subsets into two main branches: a CD127(-) branch expressing high levels of interleukin (IL) 2/15Rβ but no IL-21R, and a CD127(+) branch with the opposite phenotype. While CD was characterised by the contraction of all four innate IEL subsets, a selective expansion of CD56(-)CD127(-) and CD56(-)CD127(+) innate IEL was detected in RCDII. In vitro, in the presence of IL-15, CD56(-)CD127(-) IEL from controls and patients with CD, but not from patients with RCDII, differentiated into functional natural killer and T cells, the latter largely dependent on notch-signalling. Furthermore, compared with non-coeliac controls, CD56(-)CD127(-) IEL from patients with CD expressed more intracellular CD3ε and CD3γ and gave more pronounced T cell differentiation.
  
  
  
  Thus, we demonstrate previously unappreciated diversity and plasticity of the innate IEL compartment and its loss of differentiation potential in patients with RCDII.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Frederike
authors.initials: F
authors.lastname: Schmitz
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kooy-Winkelaar
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Anna-Sophia
authors.initials: AS
authors.lastname: Wiekmeijer
authors.forename: Martijn H
authors.initials: MH
authors.lastname: Brugman
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Mearin
authors.affiliation: Department of Gastroenterology, Free University Medical Center, Amsterdam, The Netherlands.
authors.forename: Chris
authors.initials: C
authors.lastname: Mulder
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Susana
authors.initials: S
authors.lastname: Chuva de Sousa Lopes
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Mummery
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Frank Jt
authors.initials: FJ
authors.lastname: Staal
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Bergen
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Frits
authors.initials: F
authors.lastname: Koning
mesh_terms: D017252:CD3 Complex / Q000032:analysis*; D002446:Celiac Disease / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D004386:Duodenum / Q000473:pathology*; D006801:Humans; D053699:Interleukin-7 Receptor alpha Subunit / Q000032:analysis; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis*; D012318:RNA Polymerase I; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology
chemical_list: D017252:CD3 Complex; C452842:CD3 antigen, gamma chain; D016207:Cytokines; D053699:Interleukin-7 Receptor alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; C119975:POLR1G protein, human; D012318:RNA Polymerase I
keywords: CELIAC DISEASE; CELL BIOLOGY; CELLULAR IMMUNOLOGY; GUT IMMUNOLOGY