title: Human small-intestinal epithelium contains functional natural killer lymphocytes.
abstract: OBJECTIVE
  CD3(-) non-T lymphocytes constitute the second most abundant lymphoid subset in the human small-bowel epithelium, and these CD3(-) intraepithelial lymphocytes are virtually absent in active celiac disease. Phenotypically, they resemble natural killer cells and have been termed natural killer-like intraepithelial lymphocytes. Because of the limited availability of appropriate human samples, functional studies have not yet been reported, and it is not yet clear whether these are true natural killer cells.
  
  
  METHODS
  We used magnetic bead-based purification and flow cytometry to study several aspects of normal human small-bowel natural killer-like intraepithelial lymphocytes: intracellular cytokine content (basally and after activation); ability to lyse natural killer-sensitive K562 target cells; and expression of perforins, Fas ligand, and other functional markers.
  
  
  RESULTS
  CD3(-) intraepithelial lymphocytes cultured in interleukin-2 showed a higher lymphokine-activated killer activity than CD3(+) intraepithelial lymphocytes (48%-83% lysis exerted by CD3(-) intraepithelial lymphocytes at an effector-target cell ratio of 2:1 vs. 8%-18% by CD3(+) intraepithelial lymphocytes). Perforin content correlated with this lytic potential (75% +/- 4% in CD3(-) vs. 5% +/- 4% in CD3(+) intraepithelial lymphocytes). Both CD3(-) and CD3(+) cells displayed a type I cytokine profile (interferon-gamma > tumor necrosis factor-alpha > interleukin-2; undetectable interleukin-4 and interleukin-10). In addition to their activated phenotype, subsets of natural killer-like intraepithelial lymphocytes expressed CD8alphaalpha and intracellular CD3epsilon chain, showing the existence of heterogeneity within this cell lineage.
  
  
  CONCLUSIONS
  This is the first demonstration of functional natural killer cells within the human gut epithelium. These cells might play an important role in innate mucosal immunity (host defense and tumor surveillance) and tolerance.
authors.affiliation: Department of Immunology, Hospital Ramón y Cajal, Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: León
authors.forename: Ernesto
authors.initials: E
authors.lastname: Roldán
authors.forename: Laura
authors.initials: L
authors.lastname: Sanchez
authors.forename: Cristina
authors.initials: C
authors.lastname: Camarero
authors.forename: Alfredo
authors.initials: A
authors.lastname: Bootello
authors.forename: Garbiñe
authors.initials: G
authors.lastname: Roy
mesh_terms: D000328:Adult; D019011:Antigens, CD7 / Q000032:analysis; D017252:CD3 Complex / Q000032:analysis; D002648:Child; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000276:immunology; D007421:Intestine, Small / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000032:analysis; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D019011:Antigens, CD7; D017252:CD3 Complex; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D007371:Interferon-gamma