Analysis of T cell repertoire in the liver of patients with chronic hepatitis C

Abstract

SUMMARYMany T cells infiltrate into the liver of patients with chronic hepatitis C (CH-C). They are believed to play a crucial role in the immunopathogenesis of hepatic inflammation, but their clonality and specificity are unknown. The aim of this study was to clarify the characteristics of these T cells. We analysed the complementarity-determining region (CDR)3 size lengths of T cell receptor (TCR) b-chains by size spectratyping, and determined the sequences of Vb CDR3 after subcloning Vb -specific polymerase chain reaction products. Spectratyping showed clonal expansions in all liver specimens, most of which showed more than two T cell clones. Moreover, many non-clonal T cells also accumulated in the liver. Clonality of the T cells suspected by spectratyping was confirmed by CDR3 sequencing. Although the sequences revealed no whole CDR3-shared clones among different patients, some common motif sequences were observed. Our data suggest that T cells are stimulated by several hepatitis C virus (HCV) epitopes, then accumulate in the liver of CH-C patients. Shared motifs of expanded T cell clones suggest that they might recognize the same regions of HCV peptides, but have differences due to HCV peptide mutational changes. These clones might also interact with non-clonal T cells and play a crucial role in the immunopathogenesis of CH-C.

Analysis of T-cell repertoire in hepatitis-associated aplastic anemia

“…Sing et al 25 compared the clonality of V ␤ T-cell receptor-bearing population in the liver and peripheral blood of patients with hepatitis B and found clonotypic expansions in 4 to 9 TCR V ␤ subfamilies, indicating a high restriction in the T-cell composition of liver-infiltrating lymphocytes. Similar experiments in hepatitis C and autoimmune hepatitis, 17,18,26 showed many skewed spectratype patterns in lymphocytes in the liver.Our results from the 4 cases of chronic hepatitis B and C for TCR-spectratyping analysis found a similarly highly skewed V ␤ pattern consistent with these published results (and validating our use of frozen tissue). In addition, we demonstrated that we could detect a similar skewed spectratype pattern in the livers of patients with HAA.…”

“…14,15 Analysis of the T-cell repertoire in these cases has demonstrated clonal expansions, and conserved features of antigen specificity in many of these expansions are linked to the immunopathogenesis of viral hepatitis. [16][17][18] Corresponding information concerning the T-cell immune response in HAA in liver or blood is unreported.…”

“…14,15 Analysis of the T-cell repertoire in these cases has demonstrated clonal expansions, and conserved features of antigen specificity in many of these expansions are linked to the immunopathogenesis of viral hepatitis. [16][17][18] Corresponding information concerning the T-cell immune response in HAA in liver or blood is unreported.T-cell receptor (TCR) analysis by spectratyping is a powerful tool to assess the clonal composition of the T-cell repertoire in both infectious and immune-mediated diseases. [19][20][21] The technique depends on the tissue-specific expression of certain TCRs (on T cells) and on the diversity, somatic rearrangements, and insertions at the nucleotide level that create TCR diversity.…”

Preferential suppression of trisomy 8 compared with normal hematopoietic cell growth by autologous lymphocytes in patients with trisomy 8 myelodysplastic syndrome

“…51 An effective CTL response requires T-cell engagement with the costimulatory molecules CD86 and CD28. [52][53][54] Colony inhibition by CTL in trisomy 8 MDS (which express CD86 on CD34 cells; data not shown) indicates that progenitors from these patients are competent antigen-presenting cells and susceptible CTL targets.…”

T-cell clones derived by CD3 stimulation from hepatitis C virus explanted liver tissue are not representative of dominant clones present in vivo

“…Two T-cell clones from patient 1 were identified twice (clones 1-17 and 5-11) in the cells sorted with anti-BV2. The nomenclature used to refer to each clone (for example, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] indicates that clones 1 and 17, arbitrarily assigned these numbers when cultured in microtiter plates, turned out to be identical or sibs of each other on sequence analysis. One T-cell clone from patient 3 was also isolated twice (clone 3-7).…”