Decreased level of recent thymic emigrants in CD4+ and CD8+T cells from CML patients

Institute of Hematology, Medical College, Jinan University, Guangzhou, 510632, China.
Journal of Translational Medicine (Impact Factor: 3.93). 05/2010; 8(1):47. DOI: 10.1186/1479-5876-8-47
Source: PubMed


T-cell immunodeficiency is a common feature in cancer patients, which may relate to initiation and development of tumor. Based on our previous finding, to further characterize the immune status, T cell proliferative history was analyzed in CD4+ and CD8+ T cells from chronic myeloid leukemia (CML) patients.
Quantitative analysis of deltaRec-psiJalpha signal joint T cell receptor excision circles (sjTRECs) was performed in PBMCs, CD3+, CD4+ and CD8+T cells by real-time PCR, and the analysis of 23 TRBV-D1 sjTRECs was performed by semi-nested PCR. Forty eight CML cases in chronic phase (CML-CP) were selected for this study and 17 healthy individuals served as controls.
The levels of deltaRec-psiJalpha sjTRECs in PBMCs, CD3+, CD4+, and CD8+ T cells were significantly decreased in CML patients, compared with control groups. Moreover, the numbers of detectable TRBV subfamily sjTRECs, as well as the frequency of particular TRBV-BD1 sjTRECs in patients with CML were significantly lower than those from healthy individuals.
We observed decreased levels of recent thymic emigrants in CD4+ and CD8+ T cells that may underlay the persistent immunodeficiency in CML patients.

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Available from: Grzegorz K Przybylski
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    • "The TCR/CD3 complex plays a central role in T cell activation, and the alteration of any subunits in the complex may change the T cell activation level [7-10]. An abnormal TCR repertoire, lower thymic output function and lower CD3 gene expression have been described in CML [2-6]. Alternative CD3 gene expression levels may directly represent a characteristic of lower T cell activation [2-4]. "
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    ABSTRACT: A previous study has demonstrated a significant decrease in the TCRzeta gene expression level in chronic myeloid leukemia (CML); thus, we further investigated the expression of TCRzeta-regulating factors, the distribution of the TCRzeta 3' untranslated region (3'-UTR) splice variants, and the expression level and correlation of the alternative splicing factor/splicing factor 2 (ASF/SF-2), FcepsilonRIgamma and ZAP-70 genes. TCRzeta 3'-UTR splice variants were identified in peripheral blood mononuclear cells (PBMCs) from 14 healthy individuals, 40 patients with CML and 22 patients with CML in complete remission (CML-CR) by RT-PCR. The expression level of the TCRzeta, FcepsilonRIgamma, ASF/SF-2 and ZAP-70 genes was analyzed by real-time quantitative PCR. While the expression of TCRzeta gene in the CML group was significantly lower than that in the healthy individual and CML-CR groups, a significantly higher expression of the FceRIgamma and ASF/SF-2 genes was found in the CML group. Two types of splicing forms were detected in all of the healthy individual CML-CR cases: wild type (WT) TCRzeta 3'-UTR and alternatively splieced (AS) TCRzeta 3'-UTR which have been alternatively splieced in the WT TCRzeta 3'-UTR . However, 35% of the CML cases contained only the wild type TCRzeta 3'-UTR isoform. Based on the TCRzeta 3'-UTR isoform expression characteristic, we divided the patients with CML into two subgroups: the WT+AS- CML group, containing patients that express only the wild type TCRzeta 3'-UTR, and the WT+AS+ CML group, which contained patients that expressed two TCRzeta 3'-UTR isoforms. A significantly different ASF/SF-2 and FcepsilonRIgamma gene expression pattern was found between the WT+AS- and WT+AS+CML groups. We concluded that defective TCRzeta expression may be characterized in the WT+AS-and WT+AS+CML subgroups by the different gene expression pattern. The overexpression of ASF/SF2, which alternatively splices the TCRzeta [unknown]3'-UTR, is thought to participate in feedback regulation. The characteristics of TCRzeta 3'-UTR alternative splicing may be a novel immunological marker for the evaluation of the CML immune status.
    Full-text · Article · Dec 2012 · Journal of Hematology & Oncology
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    • "During TCR rearrangement processes in the thymus, by-products in the form of sjTRECs are considered to be a valuable tool to estimate thymic function [14]. Quantitative analysis of δRec-ψJα sjTRECs provides information about total thymic output and TRBV-BD sjTRECs specific for each TRBV subfamily allow determination of the proliferative history of a particular TRBV subfamily [8-11]. In the present study, we detected both δRec-ψJα sjTRECs and TRBV-BD sjTRECs to evaluate not only the recent total naïve T-cell output but also the specific TRBV subfamily naïve T-cell output from the thymus in patients after HSCT. "
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    ABSTRACT: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) leads to a prolonged state of immunodeficiency and requires reconstitution of normal T-cell immunity. Signal joint T-cell receptor excision DNA circles (sjTRECs) are markers of developmental proximity to the thymus that have been used to evaluate thymic function related to T-cell immune reconstitution after HSCT. To assess the proliferative history in different T-cell receptor beta variable region (TRBV) subfamilies of T cells after HSCT, expansion of TRBV subfamily-naive T cells was determined by analysis of a series of TRBV-BD1 sjTRECs. sjTRECs levels were detected by real-time quantitative polymerase chain reaction (PCR) in peripheral blood mononuclear cells (PBMCs) from 43 Chinese acute leukemia patients who underwent allo-HSCT. Twenty-three TRBV-BD1 sjTRECs were amplified by semi-nested PCR. Sixteen age-matched healthy volunteers served as normal controls. sjTRECs levels were low or undetectable in the first 6 weeks after allo-HSCT and increased after 8 weeks post HSCT; however, sjTRECs levels at week 20 post-HSCT were still less than normal controls. Frequencies of TRBV subfamily sjTRECs in PBMCs from recipients at week 8 post-HSCT (29.17 ± 20.97%) or at week 16 post-HSCT (38.33 ± 9.03%) were significantly lower than those in donors (47.92 ± 13.82%) or recipients at pre-HSCT (45.83 ± 14.03%). However, frequencies of TRBV subfamily sjTRECs in recipients at week 30 post-HSCT (42.71 ± 21.62%) were similar to those in donors and recipients at pre-HSCT. sjTRECs levels in donors had a positive linear correlation with sjTRECs levels in recipients within 8-12 weeks post-HSCT. Patients with acute graft-versus-host disease (GVHD) or chronic GVHD had profoundly reduced TRECs levels during the first year post-HSCT. Frequencies of BV22-BD1 sjTRECs and BV23-BD1 sjTRECs in patients with GVHD were significantly lower than those in recipients at pre-HSCT, and the frequencies of BV22-BD1 sjTRECs in patients with GVHD were significantly lower than those in donors. Reconstitution of thymic output function resulted in a period of immunodeficiency, with low or undetectable TRECs after transplantation, although fludarabine-based dose-reduced conditioning regimens were used. GVHD could affect reconstitution of thymic output function and reduce sjTRECs levels and frequencies of TRBV-BD1 sjTRECs. Low frequency of BV22-BD1 and BV23-BD1 sjTRECs might be associated with GVHD.
    Full-text · Article · Apr 2011 · Journal of Hematology & Oncology
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    ABSTRACT: In haematological malignancy, cell-mediated immunity has been shown to be suppressed in advanced disease. This immune dysfunction may be due, in part, to altered expression of the T cell receptor (TCR)-CD3 complex. The distribution and clonality of the TCR Vbeta repertoire and the expression levels of CD3gamma, CD3delta, CD3epsilon, and CD3zeta genes in T cells from patients with multiple myeloma (MM) were investigated. Specific Vbeta subfamily primers, reverse transcription polymerase chain reaction, and the GeneScan® technique were used to analyse the expression of the TCR Vbeta subfamily and the clonality of Vbeta T cells in 11 patients with MM. Real-time reverse transcription polymerase chain reaction was used to detect the expression levels of CD3gamma, CD3delta, CD3epsilon, and CD3zeta genes in peripheral blood mononuclear cells from 19 patients with MM. The beta2-microglobulin gene was used as an endogenous reference. A total of 5-22 Vbeta subfamily T cells were detected in different patients (mean value of expressed Vbeta subfamilies was 12.55±6.11), whereas all 24 Vbeta genes were identified in all control samples. The most frequently expressed Vbeta subfamilies were Vbeta1 (100%), Vbeta2, Vbeta3, Vbeta9, Vbeta13, and Vbeta16 (81.8%), while the expression of Vbeta20 was undetectable in all MM samples. Oligoclonal expansion of one or more Vbeta subfamily of T cells was detected in all patients. Such expansions involved different MM stages, and the numbers of expanded clonal Vbeta subfamilies seemed higher in stage I/II groups than in stage III; however, there was no significant difference. Among MM samples, of the Vbeta subfamily members, Vbeta13, Vbeta1, and Vbeta21, were expanded most frequently. A significant decrease in the expression level of the CD3gamma gene was observed in MM samples; in contrast, a higher expression of CD3epsilon was found in the MM group than in the healthy group. The expression pattern of the four CD3 chains was epsilon>zeta>delta>gamma in peripheral blood mononuclear cells from MM, while a gamma>epsilon>zeta>delta expression pattern was found in healthy controls. In conclusions, the present study presents precise data on changes in the variability of Vbeta patterns and expression of TCR signal transduction molecules in MM patients compared to controls, which may be associated with immune dysfunction. This study contributes to a better understanding of the cellular immune features in MM patients.
    No preview · Article · May 2011 · Hematology (Amsterdam, Netherlands)
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