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Loss of T-Cell Multifunctionality and TCR-V? Repertoire Against Epstein-Barr Virus Is Associated With Worse Prognosis and Clinical Parameters in HIV⁺ Patients.

ABSTRACT: Epstein-Barr virus (EBV) is an oncogenic virus associated with the development of aggressive and poor-prognosis B-cell lymphomas in patients infected with human immunodeficiency virus (HIV⁺ patients). The most important risk factors for these malignancies include immune dysfunction, chronic immune activation, and loss of T-cell receptor (TCR) repertoire. The combination of all these factors can favor the reactivation of EBV, malignant cell transformation, and clinical progression toward B-cell lymphomas. The overarching aim of this study was to evaluate the frequency, phenotype, functionality, and distribution of TCR clonotypes for EBV-specific T-cell subpopulations in HIV⁺ patients at different clinical stages and for HIV⁺ patients with B-cell lymphoma, as well as to establish their association with clinical variables of prognostic value. Factors were studied in 56 HIV⁺ patients at different clinical stages and in six HIV+ subjects with diagnosed B-cell lymphoma. We found a significant decrease in all subpopulations of EBV-specific CD4⁺ T cells from HIV⁺ patients at stage 3 and with B-cell lymphoma. EBV-specific effector CD8⁺ T cells, particularly effector memory cells, were also reduced in HIV⁺ patients with B-cell lymphoma. Interestingly, these cells were unable to produce IFN-? and lacked multifunctionality in HIV+ patients. The TCR-V? repertoire, which is key for protection against EBV in healthy individuals, was less diverse in HIV⁺ patients due to a lower frequency of TCR-V?2⁺, V?4⁺, V?7.1⁺, V?9⁺, V?13.6⁺, V?14⁺, V?17⁺, V?22⁺ CD4⁺, V?14⁺, and V?17⁺ CD8⁺ T cells. HIV⁺ patients with positive plasma EBV loads (EBV⁺HIV⁺) had a noteworthy decrease in the levels of both TNF-?⁺ and multifunctional TNF-?⁺/IL-2⁺ and TNF-?⁺/IFN-?⁺ CD8⁺ T cells. Altogether, our findings demonstrate that HIV⁺ patients have significant alterations in the immune response to EBV (poor-quality immunity) that can favor viral reactivation, escalating the risk for developing EBV-associated B-cell lymphomas.

SUBMITTER: Hernandez DM

PROVIDER: S-EPMC6180205 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Loss of T-Cell Multifunctionality and TCR-Vβ Repertoire Against Epstein-Barr Virus Is Associated With Worse Prognosis and Clinical Parameters in HIV<sup>+</sup> Patients.

Hernández Diana M DM Valderrama Sandra S Gualtero Sandra S Hernández Catalina C López Marcos M Herrera Maria Victoria MV Solano Julio J Fiorentino Susana S Quijano Sandra S

Frontiers in immunology 20181004

Epstein-Barr virus (EBV) is an oncogenic virus associated with the development of aggressive and poor-prognosis B-cell lymphomas in patients infected with human immunodeficiency virus (HIV<sup>+</sup> patients). The most important risk factors for these malignancies include immune dysfunction, chronic immune activation, and loss of T-cell receptor (TCR) repertoire. The combination of all these factors can favor the reactivation of EBV, malignant cell transformation, and clinical progression towa ...[more]

PMID: 30337929

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Project description:A broad T cell receptor (TCR-) repertoire is required for an effective immune response. TCR-repertoire diversity declines with age. End-stage renal disease (ESRD) patients have a prematurely aged T cell system which is associated with defective T cell-mediated immunity. Recently, we showed that ESRD may significantly skew the TCR Vβ-repertoire. Here, we assessed the impact of ESRD on the TCR Vβ-repertoire within different T cell subsets using a multiparameter flow-cytometry-based assay, controlling for effects of aging and CMV latency. Percentages of 24 different TCR Vβ-families were tested in circulating naive and memory T cell subsets of 10 ESRD patients and 10 age- and CMV-serostatus-matched healthy individuals (HI). The Gini-index, a parameter used in economics to describe the distribution of income, was calculated to determine the extent of skewing at the subset level taking into account frequencies of all 24 TCR Vβ-families. In addition, using HI as reference population, the differential impact of ESRD was assessed on clonal expansion at the level of an individual TCR Vβ-family. CD8+, but not CD4+, T cell differentiation was associated with higher Gini-TCR indices. Gini-TCR indices were already significantly higher for different CD8+ memory T cell subsets of younger ESRD patients compared to their age-matched HI. ESRD induced expansions of not one TCR Vβ-family in particular and expansions were predominantly observed within the CD8+ T cell compartment. All ESRD patients had expanded TCR Vβ-families within total CD8+ T cells and the median (IQ range) number of expanded TCR Vβ-families/patient amounted to 2 (1-4). Interestingly, ESRD also induced clonal expansions of TCR Vβ-families within naive CD8+ T cells as 8 out of 10 patients had expanded TCR Vβ-families. The median (IQ range) number of expanded families/patient amounted to 1 (1-1) within naive CD8+ T cells. In conclusion, loss of renal function skews the TCR Vβ-repertoire already in younger patients by inducing expansions of different TCR Vβ-families within the various T cell subsets, primarily affecting the CD8+ T cell compartment. This skewed TCR Vβ-repertoire may be associated with a less broad and diverse T cell-mediated immunity.

Dataset Information

Loss of T-Cell Multifunctionality and TCR-V? Repertoire Against Epstein-Barr Virus Is Associated With Worse Prognosis and Clinical Parameters in HIV⁺ Patients.

Publications

Loss of T-Cell Multifunctionality and TCR-Vβ Repertoire Against Epstein-Barr Virus Is Associated With Worse Prognosis and Clinical Parameters in HIV<sup>+</sup> Patients.

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Dataset Information

Loss of T-Cell Multifunctionality and TCR-V? Repertoire Against Epstein-Barr Virus Is Associated With Worse Prognosis and Clinical Parameters in HIV+ Patients.

Publications

Loss of T-Cell Multifunctionality and TCR-Vβ Repertoire Against Epstein-Barr Virus Is Associated With Worse Prognosis and Clinical Parameters in HIV<sup>+</sup> Patients.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Loss of T-Cell Multifunctionality and TCR-V? Repertoire Against Epstein-Barr Virus Is Associated With Worse Prognosis and Clinical Parameters in HIV⁺ Patients.