Complementarity-Determining Region 3 Size Spectratypes of T Cell Receptor β Chains in CD8 ⁺ T Cells following Antiviral Treatment of Chronic Hepatitis B

Abstract

An increased CD8؉ T cell response to hepatitis B virus (HBV) peptides occurs between 12 and 24 weeks after starting antiviral therapy for chronic hepatitis B. It is not known whether these cells have antiviral function. The aim of this study was to determine whether clonal expansions of CD8؉ T cells at these time points predict the virological response to therapy. Peripheral blood CD8؉ T cells were obtained from 20 patients treated with lamivudine or telbivudine for chronic hepatitis B at baseline, 12 weeks, and 24 weeks. The CDR3 spectratype of each T cell receptor (TCR) ␤ chain variable region (V␤) gene family was analyzed, and the changes in the numbers of V␤ families with clonal expansions were compared in subjects with (n ‫؍‬ 12) and without (n ‫؍‬ Chronic hepatitis B (CHB) can lead to liver cirrhosis, liver failure, and liver cancer (10). CHB is always associated with replication of the hepatitis B virus (HBV) in the liver, and suppression of this replication by antiviral therapy leads to both cessation of disease activity and a decreased risk for the serious sequelae (11). Unfortunately, the suppression of viral replication induced by current antiviral therapies is not permanent in most patients, and life-long therapy is required to maintain disease inactivity. A therapeutic vaccine that permanently enhanced the patient's own immune response to the HBV would make a valuable contribution to the management of these patients.Long-term suppression of HBV replication in patients with an inactive, HBeAg-negative, chronic HBV infection is probably carried out by CD8 ϩ T cells responding to wild-type viral peptides presented by human leukocyte antigen (HLA) class I (13). Although CD8 ϩ T cells responding to peptides presented by the HLA-A*0201 allele have been widely studied, very little is known about the CD8 ϩ T cells that respond to peptides presented by other HLA class I alleles, which may be more relevant to the development of therapeutic vaccines in Asia. Boni et al. (4,5) identified an opportunity to study HBVspecific CD8 ϩ T cells from subjects with a wide range of HLA class I genotypes when they found a temporary increase in CD8 ϩ T cell responses to HBV peptides at 12 and 24 weeks after beginning antiviral therapy. Whether these responses influence the outcome of antiviral therapy is unknown. Thus, there is doubt as to whether they are genuine HBV-specific responses that might be useful targets of immunotherapy, or just HLA-and HBV-nonspecific responses resulting from TCR degeneracy (8).The complementarity-determining region 3 (CDR3) of the ␣ and ␤ polypeptides that make up the TCR are immediately 5Ј of the variable (V) sequences that distinguish the 24 families of ␤ chains and the 32 families of ␣ chains. The CDR3 regions are responsible for recognition of the antigenic peptides presented to the T cell by HLA class I. Consequently there needs to be a high level of diversity in these regions, which is generated by varying both the sequence and the number of amino acids. Variation in the number of amino ...

High serum IL-21 levels after 12 weeks of antiviral therapy predict HBeAg seroconversion in chronic hepatitis B

“…The largest difference between CR and NCR was observed at treatment week 12, which is the time when an increase in activity of the CD8 + T cells that are associated with viral control [13] can be detected. The serum IL-21 concentrations decreased with time in both the CR and NCR groups, but it was consistently higher in the CR group.…”

Quantitative analysis of T cell receptor diversity in clinical samples of human peripheral blood

“…Standard spectratyping methodology examining global diversity of TCR repertoire in human peripheral blood, however, has been based on large numbers of cells (Kochenderfer et al, 2002;Yamanaka et al, 2010;Ma et al, 2011) and, due to the absence of standardized methods of analyzing and reporting the data, the interpretation of the data generated has remained an issue. The limited T-cell numbers available in lymphopenic patients following transplant regimens have restricted spectratyping studies of immune system reconstitution.…”

High-throughput T cell receptor sequencing reveals distinct repertoires between tumor and adjacent non-tumor tissues in HBV-associated HCC

“…7 TCR diversity is closely related to treatment effectiveness and patient prognosis in different diseases. [8][9][10][11] The analysis of TCR diversity in diseases might also facilitate the elucidation of pathogenesis and the development of cellular immunotherapy approaches that target specific tumors and neoantigens. 12,13 Although tumor-infiltrating T lymphocytes have implications for tumor prognosis, information on the TCR diversity of HBV-associated liver cancer remains limited.…”