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Characteristic analysis of TCR ?-chain CDR3 repertoire for pre- and post-liver transplantation.

ABSTRACT: Liver cirrhosis of hepatitis B is an immune-related disease in which liver cells die during the body's immune system activation to clear the virus, and the progress is closely related to T lymphocytes. T lymphocyte cells recognise antigens, specifically by major histocompatibility complex (MHC), through a membrane protein T cell receptor (TCR). Here, we used high throughput immune repertoire sequencing technique to study the characteristics and diversity of the TCR repertoire between patients who underwent liver transplantation and healthy controls (NC). We sequenced the TCR ?-chain complementary-determining region 3 (CDR3) repertoire in peripheral blood mononuclear cells (PBMCs) from 6 liver transplantation patients before transplantation (Pre) and on the first (Post1) and seventh days (Post7) after transplantation along with 6 NC. We observed that the distributions of CDR3, VD indel, and DJ indel lengths were similar among the Pre, Post1, Post7 and NC groups. We found that the TCR repertoire diversity of transplantation groups was relatively lower compared to NC group. The Pre-group had more highly expanded T cell clones compared to Post1, Post7 and NC groups, and the diversity of the T cell repertoire of the Post7 group was significantly decreased compared to the Pre, Post1 and NC groups. In addition, we found our results also show that various TRBV expression increased and some public sequences at different time points after liver transplantation, and the expression levels of 3 TRBV segments and 2 TRBJ segments were also significantly different in Pre, Post1, Post7 and NC groups. Moreover, 1 aa sequence shared by all liver transplantation patients and 2 aa sequences shared by at least two groups, which may serve as biomarkers to monitor the immune status of liver transplant patients.

SUBMITTER: Yang G

PROVIDER: S-EPMC6195376 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Characteristic analysis of TCR β-chain CDR3 repertoire for pre- and post-liver transplantation.

Yang Guiqi G Ou Minglin M Chen Huaizhou H Guo Changchun C Chen Jiejing J Lin Hua H Tang Donge D Xue Wen W Li Wenlong W Sui Weiguo W Dai Yong Y

Oncotarget 20181002 77

Liver cirrhosis of hepatitis B is an immune-related disease in which liver cells die during the body's immune system activation to clear the virus, and the progress is closely related to T lymphocytes. T lymphocyte cells recognise antigens, specifically by major histocompatibility complex (MHC), through a membrane protein T cell receptor (TCR). Here, we used high throughput immune repertoire sequencing technique to study the characteristics and diversity of the TCR repertoire between patients wh ...[more]

PMID: 30349645

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Project description:BackgroundCD4 T lymphocyte activation requires T cell receptor (TCR) engagement by peptide/MHC (major histocompatibility complex) (pMHC). The TCR complementarity-determining region 3 (CDR3) contains variable ? and ? loops critical for pMHC recognition. During any immune response, tuning of TCR usage through progressive clonal selection occurs. Th1 and Th2 cells operate at different avidities for activation and display distinct transcriptional programs, although polarization may be plastic, influenced by pathogens and cytokines. We therefore hypothesized that CDR3?? sequence features may intrinsically influence CD4 phenotype during progression of a response.ResultsWe show that CD4 polarization involves distinct CDR3? usage: Th1 and Th17 cells favored short TCR CDR3? sequences of 12 and 11 amino acids, respectively, while Th2 cells favored elongated CDR3? loops of 14 amino acids, with lower predicted affinity. The dominant Th2- and Th1-derived TCR? sequences with 14 amino acid CDR3 loops and 12 amino acid CDR3 loops, respectively, were expressed in TCR transgenics. The functional impact of these TCR? transgenes was assessed after in vivo priming with a peptide/adjuvant. The short, Th1-derived receptor transgenic T cell lines made IFN?, but not IL-4, 5 or 13, while the elongated, Th2-derived receptor transgenic T cell lines made little or no IFN?, but increased IL-4, 5 and 13 with progressive re-stimulations, mirrored by GATA-3 up-regulation. T cells from primed Th2 TCR? transgenics selected dominant TCR V? expansions, allowing us to generate TCR?? transgenics carrying the favored, Th2-derived receptor heterodimer. Primed T cells from TCR?? transgenics made little or no IL-17 or IFN?, but favored IL-9 after priming with Complete Freund's adjuvant and IL-4, 5, 9, 10 and 13 after priming with incomplete Freund's. In tetramer-binding studies, this transgenic receptor showed low binding avidity for pMHC and polarized T cell lines show TCR avidity for Th17 > Th1 > Th2. While transgenic expression of a Th2-derived, 'elongated' TCR-CDR3? and the TCR?? pair, clearly generated a program shifted away from Th1 immunity and with low binding avidity, cytokine-skewing could be over-ridden by altering peptide challenge dose.ConclusionWe propose that selection from responding clones with distinctive TCRs on the basis of functional avidity can direct a preference away from Th1 effector responses, favoring Th2 cytokines.

Project description:A major cause of morbidity and mortality for patients who undergo hematologic stem cell transplantation (HSCT) is acute graft-versus-host disease (aGVHD), a mostly T cell-mediated disease. Examination of the T cell receptor (TCR) repertoire of HSCT recipients and the use of next-generation nucleotide sequencing have raised the question of whether features of TCR repertoire reconstitution might reproducibly associate with aGVHD. We hypothesized that the peripheral blood TCR repertoire of patients with steroid-nonresponsive aGVHD would be less diverse. We also hypothesized that patients with GVHD who shared HLA might also share common clones at the time of GVHD diagnosis, thereby potentially providing potential clinical indicators for treatment stratification. We further hypothesized that HSCT recipients with the same HLA mismatch might share a more similar TCR repertoire based on a potentially shared focus of alloreactive responses. We studied 2 separate patient cohorts and 2 separate platforms for measuring TCR repertoire. The first cohort of patients was from a multicenter Phase III randomized double-blinded clinical trial of patients who developed aGVHD (NCT01002742). The second cohort comprised samples from biobanks from 2 transplantation centers and the Center for International Blood and Marrow Transplant Research of patients who underwent mismatched HSCT. There were no statistically significant differences in the TCR diversity of steroid responders and nonresponders among patients with aGVHD on the day of diagnosis. Most clones in the repertoire were unique to each patient, but a small number of clones were found to be both exclusive to and shared among aGVHD nonresponders. We were also able to show a strong correlation between the presence of Vβ20 and Vβ29 and steroid responsiveness. Using the Bhattacharya coefficient, those patients who shared the same HLA mismatch were shown to be no more similar to one another than to those who had a completely different mismatch. Using 2 separate clinical cohorts and 2 separate platforms for analyzing the TCR repertoire, we have shown that the sampled human TCR repertoire is largely unique to each patient but contains glimmers of common clones of subsets of clones based on responsiveness to steroids in aGVHD on the day of diagnosis. These studies are informative for future strategies to assess for reproducible TCR responses in human alloreactivity and possible markers of GVHD responsiveness to therapy.

Dataset Information

Characteristic analysis of TCR ?-chain CDR3 repertoire for pre- and post-liver transplantation.

Publications

Characteristic analysis of TCR β-chain CDR3 repertoire for pre- and post-liver transplantation.

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