Oligoclonal expansions of CD4+ and CD8+ T-cells in the target organ of patients with biliary atresia.
OBJECTIVE
Biliary atresia is an inflammatory, fibrosclerosing neonatal cholangiopathy, characterized by a periductal infiltrate composed of CD4(+) and CD8(+) T cells. The pathogenesis of this disease has been proposed to involve a virus-induced, subsequent autoreactive T cell-mediated bile duct injury. Antigen-specific T-cell immunity involves clonal expansion of T cells expressing similar T-cell receptor (TCR) variable regions of the beta-chain (Vbeta). We hypothesized that the T cells in biliary atresia tissue expressed related TCRs, suggesting that the expansion was in direct response to antigenic stimulation.


METHODS
The TCR Vbeta repertoire of T cells from the liver, extrahepatic bile duct remnants, and peripheral blood of biliary atresia and other cholestatic disease controls were characterized by fluorescent-activated cell sorter analysis, and TCR junctional region nucleotide sequencing was performed on expanded TCR Vbeta regions to confirm oligoclonality.


RESULTS
FACS analysis revealed Vbeta subset expansions of CD4(+) and CD8(+) T cells from the liver or bile duct remnant in all patients with biliary atresia and only 1 control. The CD4(+) TCR expansions were limited to Vbeta3, -5, -9, and -12 T-cell subsets and the CD8(+) TCR Vbeta expansions were predominantly Vbeta20. Each Vbeta subset expansion was composed of oligoclonal populations of T cells.


CONCLUSIONS
Biliary atresia is associated with oligoclonal expansions of CD4(+) and CD8(+) T cells within liver and extrahepatic bile duct remnant tissues, indicating the presence of activated T cells reacting to specific antigenic stimulation. Future studies entail identifying the specific antigen(s) responsible for T-cell activation and bile duct injury.
Mack
Cara L
CL
Sections of Pediatric Gastroenterology, Hepatology and Nutrition, The Children's Hospital, University of Colorado School of Medicine, Denver, Colorado 80218, USA. cara.mack@uchsc.edu <cara.mack@uchsc.edu>
Falta
Michael T
MT
Sullivan
Andrew K
AK
Karrer
Frederick
F
Sokol
Ronald J
RJ
Freed
Brian M
BM
Fontenot
Andrew P
AP
D000293:Adolescent; D017734:Bile Ducts, Extrahepatic / Q000166:cytology / Q000276:immunology; D001656:Biliary Atresia / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002478:Cells, Cultured; D002675:Child, Preschool; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000235:genetics / Q000276:immunology; D019674:Genes, T-Cell Receptor beta / Q000235:genetics* / Q000276:immunology*; D005838:Genotype; D006650:Histocompatibility Testing; D006801:Humans; D007223:Infant; D008099:Liver / Q000166:cytology / Q000276:immunology; D043025:Oligoclonal Bands
D043025:Oligoclonal Bands