title: Small intestinal intraepithelial TCRγδ+ T lymphocytes are present in the premature intestine but selectively reduced in surgical necrotizing enterocolitis.
abstract: BACKGROUND
  Gastrointestinal barrier immaturity predisposes preterm infants to necrotizing enterocolitis (NEC). Intraepithelial lymphocytes (IEL) bearing the unconventional T cell receptor (TCR) γδ (γδ IEL) maintain intestinal integrity and prevent bacterial translocation in part through production of interleukin (IL) 17.
  
  
  OBJECTIVE
  We sought to study the development of γδ IEL in the ileum of human infants and examine their role in NEC pathogenesis. We defined the ontogeny of γδ IEL proportions in murine and human intestine and subjected tcrδ-/- mice to experimental gut injury. In addition, we used polychromatic flow cytometry to calculate percentages of viable IEL (defined as CD3+ CD8+ CD103+ lymphocytes) and the fraction of γδ IEL in surgically resected tissue from infants with NEC and gestational age matched non-NEC surgical controls.
  
  
  RESULTS
  In human preterm infants, the proportion of IEL was reduced by 66% in 11 NEC ileum resections compared to 30 non-NEC controls (p<0.001). While γδ IEL dominated over conventional αβ IEL early in gestation in mice and in humans, γδ IEL were preferential decreased in the ileum of surgical NEC patients compared to non-NEC controls (50% reduction, p<0.05). Loss of IEL in human NEC was associated with downregulation of the Th17 transcription factor retinoic acid-related orphan nuclear hormone receptor C (RORC, p<0.001). TCRδ-deficient mice showed increased severity of experimental gut injury (p<0.05) with higher TNFα expression but downregulation of IL17A.
  
  
  CONCLUSIONS
  Complimentary mouse and human data suggest a role of γδ IEL in IL17 production and intestinal barrier production early in life. Specific loss of the γδ IEL fraction may contribute to NEC pathogenesis. Nutritional or pharmacological interventions to support γδ IEL maintenance in the developing small intestine could serve as novel strategies for NEC prevention.
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee, United States of America.
authors.forename: Jörn-Hendrik
authors.initials: JH
authors.lastname: Weitkamp
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rosen
authors.affiliation: Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Koyama
authors.affiliation: Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, United States of America.
authors.forename: Duke
authors.initials: D
authors.lastname: Geem
authors.affiliation: Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, United States of America.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Denning
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee, United States of America.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Rock
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee, United States of America.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Moore
authors.affiliation: Department of Pediatrics and Steele Children's Research Center, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Halpern
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee, United States of America.
authors.forename: Pranathi
authors.initials: P
authors.lastname: Matta
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Patricia W
authors.initials: PW
authors.lastname: Denning
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D020345:Enterocolitis, Necrotizing / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000601:surgery*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature / Q000254:growth & development / Q000276:immunology*; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D007421:Intestine, Small / Q000254:growth & development / Q000276:immunology* / Q000473:pathology / Q000601:surgery; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062793:Occludin / Q000235:genetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000473:pathology
chemical_list: D020381:Interleukin-17; D062793:Occludin; D016692:Receptors, Antigen, T-Cell, gamma-delta