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. 2022 Feb 14:15:939-951.
doi: 10.2147/JIR.S347702. eCollection 2022.

Characterization of the TCR β Chain Repertoire in Peripheral Blood from Hepatitis B Vaccine Responders and Non-Responders

Jiezuan Yang  1 , Yongtao Li  1 , Jing Ye  2 , Ju Wang  1 , Haifeng Lu  1 , Xinsheng Yao  3
Affiliations

Characterization of the TCR β Chain Repertoire in Peripheral Blood from Hepatitis B Vaccine Responders and Non-Responders

Jiezuan Yang et al. J Inflamm Res. .

Abstract

Background: Hepatitis B (HepB) vaccination can effectively prevent the prevalence of hepatitis B virus (HBV) infection. However, the incidence of vaccination failure is about 5~10% and the underlying molecular mechanisms are poorly understood. T cells have an essential role in the recipient's immune response to vaccine, which could be elucidated by high-throughput sequencing (HTS) and bioinformatics analysis.

Methods: We conducted HTS of the T cell receptor β chain (TRB) complementarity-determining region 3 (CDR3) repertoires in eighteen positive responders (responders) and 10 negative responders (non-responders) who all had HepB vaccination, the repertoire features of BV, BJ and V-J genes and their diversity, respectively, were compared between the positive and negative responders using the Mann-Whitney test. Moreover, the relatively conserved motifs in CDR3 were revealed and compared to those in the other group's report.

Results: The diversity of TRB CDR3 and the frequencies of BV27 and BV7-9 are significantly increased for HepB vaccine responders compared to those in non-responders. The motifs of CDR3s in BV27/J1-1, BV27/J2-5, and BV7-9/J2-5, respectively, were most expressed as "NTE", "QETQ", and "GG-Q (E)-ETQ". Moreover, the motif "KLNSPL" was determined in nearly 80% CDR3s in BV27/J1-6 from HepB vaccine responders for the first time.

Conclusion: Our results present the comprehensive profiles of TRB CDR3 in the HepB vaccine responders and non-responders after standard vaccination protocol and determine the relatively conservative motifs of CDR3s that may respond to the HepB vaccine. Further results suggest that the profile of TRB repertoire could distinguish the HepB vaccine responders from non-responders and provide a new target for optimizing and improving the efficiency of the HepB vaccine.

Keywords: complementarity-determining region 3; hepatitis B surface antibody; hepatitis B vaccination; high-throughput sequencing; immune repertoire.

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Conflict of interest statement

The authors report no conflicts of interest for this work.

Figures

Figure 1
Figure 1
Clonal distribution and diversity of TRBV repertoires in HepB vaccine responders and non-responders. (A) The number of unique CDR3s. (B) Ratio of counts between unique CDR3 and total CDR3s identified in HepB vaccine responders and non-responders. Data points represent the counting ratio between unique CDR3 and total CDR3 in the TR repertoire of each individual. The bars depict the mean (±SEM) of the groups when data are non-normal distribution, and the differences compared using the Mann–Whitney test. (C) The distribution of TRBV frequencies are presented through the measurement of Shannon index (diversity) and (D) clonality. Each dot represents the diversity or clonality of each subject, and bars show the mean (±SD) of the groups. The differences are compared using two-tail unpaired t-test when data are normal distribution.
Figure 2
Figure 2
Comparison of the frequency, counts, and length distribution of TRB CDR3 between HepB vaccine responders and non-responders. (A) Cumulative frequency of top 100 CDR3s (CF100) in HepB vaccine responders and non-responders. Data points represent the CF100 in the total repertoire of each subject, and bars depict the mean (±SD) of the percentages of each subject. (B) The number of CDR3s with different frequency distribution range. Data are presented as Box and whiskers (5–95% percentile) of each subject, in which the middle solid line is the median count of CDR3s, the highest and lowest horizontal lines represent the 5th, and 95th percentiles. The p values of comparisons were calculated using the Mann–Whitney test, *p < 0.05. (C) Cumulative frequency of CDR3 distributions range. Data are presented as mean (±SD) of each subject using histogram. Normality of average value of cumulative frequency is detected by the Shapiro–Wilk test. (D) Comparison of the average of CDR3 length distribution between HepB vaccine responders and non-responders. Data points represent the CDR3 length average of each individual, and bars depict the mean (±SD) of subjects.
Figure 3
Figure 3
Distribution features of CDR3 length, TRBV, and BJ gene of the T cell clonotypes in HepB vaccine responders and non-responders. (A) The profile of CDR3 length distribution. (B) Percentage frequency of TRBV sub-families merged. The number after “*” represents the number of sub-families in this TRBV family, such as TRBV7*8 means the TRBV7 family including 8 sub-families. (C) The detail of 8 sub-families of the TRBV7. (D) Thirteen BJ families. Data show mean (± SEM) frequency of each subject. Data were compared using the Mann–Whitney test, *p < 0.05. Among all TRBV families, only the TRBV27 and BV7-9 have significantly different expression between the two groups (p = 0.0338, 0.0258), and the TRBV17, BV23-1, BV26 are low expressions or even undetectable in the most individuals.
Figure 4
Figure 4
Profile of TRBV/BJ combination in HepB vaccine responders and non-responders. (A) Heat map of V-J gene combinations for the HepB vaccine responders, and (B) non-responders from IMGT/Stat clonotype analysis shows there are some different V-J gene combinations between the two groups. Such as, the 60 TRBV families are obviously clustered into four groups in non-responders, and the 13 TRBJ families are obviously divided into two groups, which both are not found in responders.
Figure 5
Figure 5
Comparison of the characteristics of TRBV V/D/J gene segment combinations between HepB vaccine responders and non-responders. The rearranged number of different gene segments (V/D/J) recombination of each subject for V-J genes (A), V/D/J genes (B), V(CDR3)J genes (C), and frequency distribution of V/D/J combinations (D). Each dot represents the number of each subject, and bars show the mean (±SEM). The differences are compared using the Mann–Whitney test.
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Grants and funding

The work was supported by the National Key Research and Development Program of China (2021YFC2301804), Zhejiang Provincial Natural Science Foundation of China (LY19H190004), and National Natural Science Foundation of China (82072357).