title: Exclusive increase of CX3CR1+CD28-CD4+ T cells in inflammatory bowel disease and their recruitment as intraepithelial lymphocytes.
abstract: BACKGROUND
  CX3CL1/Fractalkine (FKN) has been reported to play important roles in various inflammatory diseases. We examined the role of FKN and its receptor CX3CR1 in T-cell migration in the inflammatory bowel diseases (IBDs), ulcerative colitis (UC) and Crohn's disease (CD).
  
  
  METHODS
  CX3CR1 expression on peripheral CD4(+) cells from normal controls (NL n = 24) and IBD patients (UC n = 28, CD n = 26) was examined using flow cytometry. CX3CR1(+)CD4(+) T cells were further characterized for surface antigens, cytokine production, and cytotoxic granule release by flow cytometry and ELISA. FKN expression in 53 colonic biopsy specimens (UC n = 20, CD n = 23, NL n = 10) was analyzed by quantitative PCR and immunohistochemistry. Isolated lamina propria and intraepithelial lymphocytes were also analyzed by flow cytometry (UC n = 10, CD n = 10, NL n = 6).
  
  
  RESULTS
  CX3CR1(+)CD4(+) cells were increased in IBD while they were virtually absent in controls. Upregulation of CX3CR1 on CD4(+) T cells was positively correlated with disease activity. These unique T cells expressed markers for both effector memory and cytotoxic cells. Interestingly, CX3CR1 was expressed on CD4(+) T cells lacking CD28. CX3CR1(+)CD28(-)CD4(+) cells produced more IFN-gamma and TNF-alpha than CX3CR1(-) counterparts and released cytotoxic granules. FKN mRNA was upregulated in inflamed colonic tissues and robust expression of FKN was immunohistochemically observed on epithelial cells. Although CX3CR1(+) CD4(+) cells could not be detected in the gut, CD28(-)CD4(+) cells were found in IBD mainly as intraepithelial lymphocytes.
  
  
  CONCLUSIONS
  FKN/CX3CR1 may contribute to the pathogenesis of IBD through the emergence of unique CX3CR1(+)CD28(-)CD4(+) T cells that can act both as proinflammatory and cytotoxic cells.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Susumu
authors.initials: S
authors.lastname: Okamoto
authors.forename: Yuko
authors.initials: Y
authors.lastname: Iwakami
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakazawa
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Hisamatsu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Chinen
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kamada
authors.forename: Toshio
authors.initials: T
authors.lastname: Imai
authors.forename: Hidemi
authors.initials: H
authors.lastname: Goto
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018106:CD28 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D000073883:CX3C Chemokine Receptor 1; D002465:Cell Movement / Q000276:immunology; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000209:etiology / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D019707:Receptors, Chemokine / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018106:CD28 Antigens; D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; D016207:Cytokines; D008565:Membrane Proteins; D019707:Receptors, Chemokine