Revised: June 18, 2026
Accepted: July 7, 2026
Published online: July 27, 2026
Processing time: 77 Days and 21.4 Hours
Chronic hepatitis B (CHB) remains a critical global health challenge, with few patients achieving spontaneous clearance of hepatitis B surface antigen (HBsAg), which is a key indicator of functional cure. T cell plays an im
To compare T cell receptor (TCR) fingerprints between patients with or without HBsAg clearance after pegylated interferon alpha-2b (PegIFNα-2b) added on nucleos(t)ide analogues (NAs).
In this observational study, peripheral blood mononuclear cells (PBMCs) were isolated from six comparable CHB patients who achieved HBsAg clearance (Group-C) or not (Group-NC) after 48 weeks of PegIFNα-2b added to NA therapy. Patients in Group-C and Group-NC had comparable age, gender, baseline hepatitis B virus (HBV) DNA, HBsAg, hepatitis B envelop antigen (HBeAg), total bilirubin, alanine aminotransferase (ALT) and cirrhosis status. All patients had received at least one year of NA before PegIFNα-2b therapy. TCR repertoire profiles (fingerprints) were screened and compared by RNA sequencing and bioinformation analysis between the two groups.
Six male patients without cirrhosis were enrolled in this study, with three patients in each group. 200 ng of RNA from each PBMC sample was extracted for standard RNA sequencing for construction of a complementary DNA library. Baseline levels of HBsAg, HBeAg, HBV DNA (< 50 IU/mL) and ALT prior to PegIFNα-2b therapy showed no statistic differences between the two groups (P > 0.05). It was found that compared to Group-NC, Group-C had significantly higher TCR diversity in both α and β chain, including more unique clonotypes (P = 0.017, P = 0.038 respectively), more repertoire overlap (P = 0.002, P = 0.002 respectively), a broader complementarity-determining region3 length distribution, and higher Chao1 index (P = 0.016, P = 0.048 respectively).
Patients with HBsAg clearance had a more diverse and robust T cell response, which may correlate with HBsAg clearance status. These immune signatures may serve as potential reference indicators for PegIFNα-2b treatment response in CHB patients.
Core Tip: This study compared T cell receptor (TCR) fingerprints of chronic hepatitis B (CHB) patients with or without hepatitis B surface antigen (HBsAg) clearance following treatment with nucleos(t)ide analogues combined with pegylated interferon alpha-2b (PegIFNα-2b). No baseline virological/biochemical differences were found between the groups. Patients achieving HBsAg clearance exhibited markedly higher TCR α/β chain diversity, more unique clonotypes and greater repertoire overlap. These immune signatures may serve as potential reference indicators for PegIFNα-2b treatment response in CHB patients.
- Citation: Hao KY, Tang L, Chen GB, Guo W, Wang ZH, Mao LP, Yu YC. Effects of pegylated interferon on T cell receptor fingerprints in chronic hepatitis B patients with/without surface antigen clearance. World J Hepatol 2026; 18(7): 123089
- URL: https://www.wjgnet.com/1948-5182/full/v18/i7/123089.htm
- DOI: https://dx.doi.org/10.4254/wjh.123089
Chronic infection of hepatitis B virus (HBV), which can lead to chronic hepatitis B (CHB), fibrosis, cirrhosis, liver failure, hepatocellular carcinoma (HCC) and related complications such as portal hypertension and esophageal-gastric variceal bleeding, remains a critical global health threat, especially in China[1,2]. A large number of clinical studies have shown that antiviral treatment of CHB can suppress HBV replication, reverse liver inflammation and fibrosis, and decrease risks of cirrhosis and HCC[3,4]. Sustained clearance of hepatitis B surface antigen (HBsAg), which usually means the achie
How to optimize individualized antiviral treatment strategies for different CHB patients to get HBsAg clearance is a hot topic. Pegylated interferon alpha (PegIFN-α) is considered an effective immunomodulator that can promote HBsAg clearance, particularly in patients with low baseline HBsAg (less than 1500 IU/mL) and HBV DNA (undetectable or below 1 × 103 IU/mL)[7,8]. Subcutaneous injection of PegIFN-α once weekly for 48-72 weeks, either in monotherapy or combination with oral NA once daily for a long duration at least one year, had been proven to induce a significantly higher serological response (e.g., HBsAg clearance or HBsAg/hepatitis B surface antibody seroconversion) than NA monotherapy[5,9]. Data from the Chinese Mount Everest Project for Clinical Cure of CHB from April 2018 to May 2025 showed that in patients who had baseline HBsAg < 1500 IU/mL, undetectable HBV DNA and had finished at least 36 weeks of PegIFN-α in addition to continuous NA therapy, up to 33.8% (n = 10240) achieved HBsAg clearance at week 48[10]. Another research from China showed that for patients with NA-related virological suppression, switching to a limited course of PegIFN-α significantly increased the rate of HBsAg seroclearance to 20% of those with baseline HBsAg < 1500 IU/mL[11].
However, the therapeutic effect of PegIFN-α varies markedly in different patients, even if they have similar favorable baseline HBsAg and HBV DNA loads. Accordingly, another concern is the internal mechanisms that lead to the different responses to PegIFN-α in patients with similar baseline characteristics. It is known that IFN-α has both direct and indirect antiviral activities. The direct antiviral activity refers to regulation of the expression of multiple intrahepatocellular genes and the translation of proteins, including APOBEC3 cytidine deaminase, human myxovirus resistance 2 protein, tripartite motif-containing protein 22, interferon-stimulated gene 20 and myeloid differentiation primary response 88, which can interfere in several stages of the HBV life cycle, thus inducing a non-cytolytic antiviral state in hepatocytes[5,12,13]. The indirect antiviral activity refers to the complex immune regulatory functions of IFN-α on innate and adaptive immune systems[14,15], including activation of macrophages, natural killer cells (NKs), dendritic cells (DCs), and T cells, and induction of a variety of cytokines, such as interleukin (IL)-1β, IL-6, IL-12, IL-15, tumor necrosis factor-α, and IFN-γ[5,12,13]. The immune regulatory activities can suppress HBV through both non-cytolytic mechanism by antiviral cytokines and cytopathic mechanism by HBV-specific CD8+ T cells[5,16].
Among these immunological factors, changes in T cell patterns and functions are a concern, which is largely reflected by the crucial diversity of T cell receptors (TCR) repertoire (TCR fingerprints). CHB patients with active inflammation have been shown to have a clonal expansion associated with several HBV epitopes[17,18]. However, to date, no studies have investigated the difference in TCR fingerprints between patients with or without HBsAg clearance. In this study, two strictly matched groups of CHB patients, one with and the other without HBsAg clearance after PegIFNα-2b-on-NA treatment, were selected to compare the key differences in TCR fingerprints, which may be associated with HBsAg clearance.
This single-center, prospective, open-label, real-world observation cohort study was conducted from 2019 to 2024 at the Center of Hepatology and Department of Infectious Disease in Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University. The study complied with the rules of Good Clinical Practice and the Declaration of Helsinki, and was approved by the hospital Ethics Committee (No. DZQH-KYLL-23-0201). All patients provided informed written consent prior to study enrollment. This study was registered in the Chinese Clinical Trial Registry (No. ChiCTR2300071650).
Inclusion criteria: (1) Age from 18 to 70 years old; (2) Diagnosed with CHB; (3) Receiving long-term entecavir, tenofovir disoproxil fumarate or tenofovir alafenamide fumarate for at least one year prior to the addition of PegIFNα-2b, which was administered for ≥ 48 weeks; and (4) HBsAg levels were ≤ 1000 IU/mL prior to treatment.
Exclusion criteria: (1) Concurrent coinfection with hepatitis A, C, D or E virus or human immunodeficiency virus; (2) Evidence of liver decompensation; alcohol or drug abuse; autoimmune diseases; (3) Severe metabolic diseases; a history of severe psychiatric disease, particularly depression; (4) Severe dysfunction of any other organ; pregnant or to be pregnant in 6 months before PegIFNα-2b treatment; lactating women; (5) Evidence of carcinoma; and (6) Any other situa
All patients completed a minimum 48-week course of PegIFNα-2b combined with NA therapy. Patients were stratified into two cohorts based on the primary endpoint of HBsAg seroclearance (two consecutive negative HBsAg results obtained at a 24-week interval). Group-C: Patients who achieved confirmed HBsAg clearance after 48 weeks of combination therapy; Group-NC: Patients who remained HBsAg-positive after 48 weeks of combination therapy. After screening all inclusion and exclusion criteria and obtaining supplementary RNA sequencing informed consent, three participants were finally enrolled in each group for comparative analysis of TCR repertoire.
Serum HBsAg, hepatitis B envelop antigen (HBeAg) and anti-hepatitis B core antigen were quantified using the architect HBV assay (Abbott Laboratories, Illinois, United States), which had a linear range of detectable HBsAg levels from
RNA extraction and quality assessment: Peripheral blood mononuclear cells (PBMCs) were isolated from 10 mL of peripheral blood from each patient and subsequently frozen at -70 °C. Total RNA was extracted from the PBMCs using the TRIzol reagent, following the manufacturer's protocol. The quality and concentration of the extracted RNA were evaluated using a NanoDrop spectrophotometer (Waltham, MA, United States) and an Agilent Bioanalyzer (SantaClara, CA, United States).
Library preparation: Two hundred ng of RNA from each PBMC sample was extracted for standard RNA sequencing for construction of a complementary DNA (cDNA) library, and a panel of unique molecular identifiers was incorporated into the cDNA to uniquely label each original RNA molecule, thereby reducing amplification bias.
PCR amplification and data processing: Subsequently, multiplex PCR was employed to amplify the variable (V), diversity (D), and joining (J) gene segments of the TCR, resulting in the generating of raw FASTQ files. The raw TCR-Seq reads were initially processed using custom scripts to convert the FASTQ files into the format required by MIGEC software (v1.2.9). Following the MIGEC processing, the resulting data were analyzed using Immunarch (v0.6.5) in R (v4.0.3) for downstream analysis.
RNA-sequencing data analysis: Immunarch was employed to perform clonotype analysis, diversity assessment, and repertoire overlap evaluation. Key metrics such as clonotype abundance, diversity indices (e.g., Chao1 indices), and V(D)J gene usage were calculated to provide comprehensive insights into the TCR repertoire.
χ2 tests were employed to determine differences between categorical variables. Continuous normally distributed variables were analyzed using student’s t-tests, while non-normally distributed variables were assessed with the Kruskal-Wallis H test. All analyses were conducted using SPSS software version 23.0. Significance tests were two-sided, and a P value less than 0.05 was considered significant. In RNA-sequencing, a P value cutoff of 0.05 and a fold-change cutoff of 2 were used to evaluate the statistical significance of gene expression differences.
A total of 103 patients received PegIFNα-2b therapy. In 43 patients, the PegIFNα-2b treatment course was shorter than 48 weeks, 27 failed to complete scheduled laboratory tests at the required time points, and 15 declined to participate in the study. After matching for age, gender, levels of HBsAg, HBV DNA and HBeAg, an additional 12 patients were excluded. A total of six patients were finally enrolled in the study, with three patients in each group. The baseline demographic characteristics of patients in the two groups were not significantly different (P > 0.05, Table 1). In Group-C, the time intervals from the first HBsAg clearance to blood collection were 0 year, 1year and 3years, respectively. In Group-NC, the time intervals were 0 year, 1year and 0 year, respectively. In Group-C, the anti-HBs levels were 546.12 mIU/mL, 3.66 mIU/mL and 0.87 mIU/mL respectively, while in Group-NC, the levels were 0.09 mIU/mL, 0 mIU/mL and 0 mIU/mL, respectively. The data volumes for TCR-sequencing were 4.94 Gbp, 5.69 Gbp, 4.16 Gbp in Group-C, while they were 4.13 Gbp, 7.81 Gbp, 4.18 Gbp in Group-NC.
| Indexes | Group-C (n = 3) | Group-NC (n = 3) | t value | P value |
| Age (year) | 40.00 ± 7.55 | 40.67 ± 8.33 | -0.10 | 0.92 |
| Male (n) | 3 | 3 | / | 1.00 |
| HBsAg (media, mIU/mL) | 288.88 ± 208.75 | 106.44 ± 52.69 | 1.47 | 0.22 |
| HBeAg (S/CO) | 0.43 ± 0.05 | 0.54 ± 0.23 | -0.82 | 0.47 |
| Anti-HBc (S/CO) | 7.96 ± 1.18 | 8.98 ± 1.14 | -1.08 | 0.34 |
| HBV DNA < 50 IU/mL (%) | 100 (3/3) | 100 (3/3) | / | 1.00 |
| ALT (U/L) | 30.33 ± 17.21 | 23.67 ± 4.73 | 0.65 | 0.55 |
| Total bilirubin (μmol/L) | 16.77 ± 2.48 | 13.83 ± 1.32 | 1.81 | 0.15 |
| Cirrhosis (%) | 0 (0/3) | 0 (0/3) | / | 1.00 |
TCR-sequencing analysis was carried out to elucidate the role of TCR diversity and clonal expansion under PegIFNα-2b-on-NA antiviral therapy, focusing on the differences in TCRα chains. Several key differences between Group-C and Group-NC were found.
Firstly, the number of unique clonotypes in Group-C was significantly higher than in Group-NC (Figure 1A, P = 0.017), as demonstrated by the bar chart comparing clonotype counts between the two groups (Figure 1B).
Next, the public repertoire overlap was examined to assess the sharing of TCRα chain sequences among samples from the different groups. The overlap values in Group-C and Group-NC were 2124 (1936-2427) and 377 (327-849), respectively (Figure 1C, P = 0.002), suggesting the presence of greater shared TCRα chain sequences in Group-C. Additionally, rare clonotype proportion analysis was used to evaluate the distribution of clonotypes at specific counts, and a higher proportion of rare clonotypes was found in Group-C than in Group-NC (Figure 1D). The relative proportion of clonotypes across different frequency categories was further quantified and illustrated by a bar chart (Figure 1E), and higher diversity in the lower frequency ranges in frequency 1 (P = 0.013) and frequency 2-3 (P = 0.012) was found in Group-C.
Finally, we analyzed the distribution of complementarity-determining region 3 (CDR3) lengths to evaluate the diversity of TCRα chain sequences. The histogram in Figure 1F showed that Group-C had a broader CDR3 length distribution (length 14, approximately 6500 clonotypes, P < 0.05).
A further detailed comparative analysis showed that the usage frequency of certain genes (especially TRAV5, P < 0.05) was significantly higher in Group-C compared to Group-NC (Figure 2A). The correlation heatmap of gene usage was showed in Figure 2B.
Chao1 indices was commonly used to provide a more comprehensive evaluation of biodiversity that accounts for unobserved species and showed a significant difference in sample diversity between the two groups (Figure 2C and D), with Group-C showing significantly higher diversity than Group-NC (P = 0.016, Figure 2E). Furthermore, the proportional distribution of different clonotypes within each sample also showed significant differences between the two groups (Figure 2E and F). The clonotype distribution in Group-C was more uniform and diverse, while relatively concentrated in Group-NC.
We also examined the clonotype diversity and distribution of TCRβ chains in both groups, and found that the number of unique clonotypes of TCRβ chains was significantly higher in Group-C (TCR1-3) compared to Group-NC (TCR4-6) (Figure 3A). This finding indicated a broader TCRβ repertoire in Group-C, and was substantiated by the average clonotype counts, which were significantly elevated in Group-C (P = 0.038) (Figure 3B).
The public repertoire overlaps analysis on each sample further revealed that Group-C shared 341 (310-499) clonotypes, while Group-NC only shared 58 (25-250) clonotypes (Figure 3C, P = 0.002). When examining the rare clonal proportions, a higher proportion of clonotypes with specific counts, particularly in the intermediate frequency ranges (frequency 1, P = 0.026) was found in Group-C compared to Group-NC (Figure 3D and E).
The distribution of CDR3 lengths among the clonotypes in both groups further supported the above-mentioned observations, with Group-C displaying a broader range of CDR3 lengths (length 15, approximately 6200 clonotypes, P < 0.05), indicative of greater diversity (Figure 3F).
Further examination of TCRβ chain usage and clonotype distribution revealed significant differences between Group-C (TCR1-3) and Group-NC (TCR4-6) (Figure 4). Compared to Group-NC, Group-C exhibited notably higher frequencies of certain TCRβ genes, such as TRBV7-2 and TRBV20-1 (P < 0.05, Figure 4A). This differential gene expression may reflect the specificity of immune responses between the two groups. The correlation heatmap of gene usage is showed in Figure 4B. Diversity estimation based on the Chao1 indices revealed significantly higher sample biodiversity in Group-C than Group-NC (P = 0.048, Figure 4C and D), which was consistent with our earlier findings of greater clonotype diversity in Group-C. Clonotype tracking further demonstrated that major clonotypes in Group-C were more uniformly distributed across different samples, whereas clonotypes in Group-NC were concentrated in a few samples (Figure 4E and F).
The decrease in HBsAg or seroconversion in CHB patients is closely related to the host's immune function, which can be enhanced by PegIFNα-2b treatment through various mechanisms[19]. However, the most crucial mechanism is the impact on T cell function. The TCR fingerprint is an important indicator reflecting the function of T cells and has potential value in providing clues to the response to interferon antiviral therapy. However, to date, few studies have investigated the impact of interferon treatment on the changes in TCR fingerprints of CHB patients. Therefore, in this study, patients who achieved HBsAg clearance after PegIFNα-2b treatment (Group-C) and those who did not (Group-NC) were selected to compare the differences in TCR fingerprints, in order to lay the foundation for evaluating their potential value associated with HBsAg clearance and optimize the future antiviral treatment plan. In line with our primary hypothesis, our study demonstrated that patients who achieved HBsAg clearance had a significantly higher TCR repertoire diversity compared to those who failed to achieve HBsAg clearance. These findings may provide clues regarding T-cell-mediated immunity in achieving HBsAg clearance.
To minimize the impact of confounding factors on TCR diversity, rigorous screening during the enrollment of patients was conducted. It is well known that TCR repertoire and the adaptive immune system may vary with gender and age[20]. As a result, CHB patients with the same gender and comparable age were considered during enrollment in this study. In addition, it was necessary to consider that both the Group-NC and Group-C should receive a minimum of 48 weeks of PegIFNα-2b-on-NA treatment, and their baseline viral and serological characteristics should be similar. However, this strict matching strategy inevitably restricted the number of eligible participants from an initial 103-patient cohort screened, resulting in a small exploratory sample size of six male patients. In future, a large sample including female patients should be enrolled to expand general applicability.
Increased TCR diversity improved the immune response[21-23]. The CDR3 segment was distinctive for each T-cell lineage and encoded the component of the receptor that facilitates the majority of TCR interactions with antigenic peptides presented by the major histocompatibility complex[22]. Longer CDR3 segments expand the structural diversity of the antigen-binding pocket, enabling T cells to recognize a broader spectrum of mutated and conserved HBV epitopes covering preS, S, core and polymerase proteins. In our study, Group-C patients displayed a significantly wider CDR3 length distribution centered at 14 amino acids, which functionally translates to a larger pool of T cell clones capable of capturing heterogeneous viral antigens and resisting HBV mutational escape; by contrast, compressed CDR3 length distribution in Group-NC restricts epitope recognition breadth and weakens anti-viral immune surveillance.
The clonal overlap value reflects the shared TCR repertoire reservoir across individuals. TCR sequencing showed low clonal overlap between tissues during the effector response[24]. Therefore, the extremely low overlap value in Group-NC patients was found. Higher inter-individual clonal overlap in Group-C indicated that reconstruction of shared antiviral T cell clones was achieved in patients with HBsAg clearance. The stratification by clonal frequency divided peripheral TCR repertoires into high-frequency dominant clones and low-frequency rare clones, the two subsets had opposing immune phenotypes in persistent viral infection. High-frequency oligoclonal expansion, the dominant feature observed in Group-NC, was a hallmark of T cell exhaustion: Repeated chronic stimulation by persistent HBV antigen drives massive proliferation of limited T cell clones, which gradually upregulate multiple inhibitory receptors and proliferative and cytotoxic capacity is lost. However, low-frequency TCR clones mainly consist of naive and early memory T cells with intact functional potential, serving as the core reserve for multi-antigen recognition[25]. Our data confirmed that Group-C harbored significantly expanded low-frequency clones at tier 1 and tier 2-3 frequency subgroups. The abundant low-frequency polyclonal pool provides a large standby repertoire that can rapidly proliferate when encountering viral antigens, forming the immunological foundation for sustained HBV clearance. Combined analysis of TCR α and β chains eliminates the one-sided bias caused by single-chain detection.
PegIFNα-2b restores broad TCR polyclonal diversity to expand the reservoir of HBV-reactive T cell precursors, which is a prerequisite for launching multi-epitope antiviral responses[26,27]. PegIFNα-2b treatment could boost immunity to clear the HBV reservoir of infected hepatocytes, which is crucial for achieving the goal of HBsAg clearance[28]. Interestingly, a recent study reported that CD300A+CD8+T expression, a well-documented ability to recognize phosphatidylserine and phosphatidylethanolamine in plasma membrane[29], was markedly elevated in all patients who received PegIFN therapy and achieved FC when compared with the non-FC group. The T cells in the FC-group had significant HBV-specific clonal expansion and enhanced cytotoxic effector functions. This indicated that a robust immune response had been induced in patients who achieved HBsAg clearance[25]. Only when paired with a diversified TCR repertoire can CD300A signaling exert robust antiviral effects; oligoclonal exhausted T cells in Group-NC did not benefit from this cytotoxic receptor modulation despite interferon stimulation, explaining the lack of HBsAg clearance in this subgroup.
PegIFNα-2b exerts independent regulatory effects on B cell maturation, memory B cell formation and anti-HBs antibody production neutralization, as documented in prior immunological research[30]. Humoral immunity complements cellular TCR-mediated surveillance by neutralizing circulating virions and blocking hepatocyte reinfection. Combining the T and B cell diversity, viral marker and biochemical markers may help construct better models for FC.
Although this study revealed several interesting findings regarding in the TCR repertoire related to HBsAg clearance, it is important to acknowledge its limitations. Firstly, in the real world, some CHB patients were not able to complete the 48-week PegIFNα-2b therapy, resulting to a limited number of patients eligible for enrollment during screening. While some of these patients singed the informed consent, their numbers were insufficient for robust analysis. Secondly, the small sample size restrict the applicability of the relevant findings to more patients. Thirdly, none of the patients resided in the city where the hospital is located, and their follow-up was voluntary. Consequently, blood samples for TCR testing could not be collected at the time when HBsAg first negative. Fourthly, our study did not analyze PBMC samples prior to PegIFNα-2b therapy, making it difficult to ascertain whether the significant differences in TCR clone characteristics between the two groups were preexisting, induced by interferon therapy, or a combination of both. The patients included in this study received different types of NAs, including entecavir, tenofovir disoproxil fumarate and tenofovir alafenamide fumarate which may have influenced the results. Additionally, we did not investigate the differences in human leukocyte antigen and HBV-specific TCR clones. In future, larger sample sizes, female participants, multi-center cohorts, and paired pre- and post-treatment samples are required to validate the present observations.
Our findings suggest that a more diverse and robust T cell response, characterized by higher TCR diversity and clonal expansion, is associated with successful HBsAg clearance following PegIFNα-2b-on-NA treatment. The layered TCR repertoire signatures identified in this exploratory matched cohort have potential auxiliary value for individualized interferon therapy of CHB, with two clinical application directions worthy of further exploration. First, serial dynamic monitoring of TCR diversity, CDR3 Length distribution and low-frequency clonal abundance during PegIFNα-2b treatment may provide supplementary immune reference information in order to judge treatment response trajectory in real time. Clinicians could combine longitudinal TCR metrics with conventional serological and virological markers to adjust interferon treatment duration or dosage for individual patients. Second, sustained maintenance of broad TCR polyclonal diversity after interferon cessation may act as a surrogate marker for durable off-treatment immune control, helping identify patients who can safely discontinue antiviral therapy without HBV reactivation risk. Reduction of HBsAg levels is accompanied by clonal expansion of CD4, CD8 T cells and plasma cells in the liver upon HBV small interfering RNA and subsequent therapeutic vaccination[31]. Future research with larger cohorts, male and female subjects, baseline and after treatment TCR repertoire is needed to elucidate the internal mechanisms in different CHB patients.
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