Exclusive increase of CX3CR1+CD28-CD4+ T cells in inflammatory bowel disease and their recruitment as intraepithelial lymphocytes

Inflamm Bowel Dis. 2007 Jul;13(7):837-46. doi: 10.1002/ibd.20113.


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.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • CD28 Antigens / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / physiology*
  • CX3C Chemokine Receptor 1
  • Cell Movement / immunology
  • Chemokine CX3CL1
  • Chemokines, CX3C / metabolism*
  • Cytokines / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Humans
  • Inflammatory Bowel Diseases / etiology
  • Inflammatory Bowel Diseases / immunology*
  • Intestinal Mucosa / immunology*
  • Male
  • Membrane Proteins / metabolism*
  • Middle Aged
  • Receptors, Chemokine / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction


  • CD28 Antigens
  • CX3C Chemokine Receptor 1
  • CX3CL1 protein, human
  • CX3CR1 protein, human
  • Chemokine CX3CL1
  • Chemokines, CX3C
  • Cytokines
  • Membrane Proteins
  • Receptors, Chemokine