T-bet and Eomes Are Differentially Linked to the Exhausted Phenotype of CD8+T Cells in HIV Infection

Marcus Buggert, Johanna Tauriainen, Takuya Yamamoto, Juliet Wairimu Frederiksen, Martin A. Ivarsson, Jakob Michaelsson, Ole Lund, Bo Hejdeman, Marianne Jansson, Anders Sonnerborg, Richard A. Koup, Michael R. Betts, Annika C. Karlsson

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    Abstract

    CD8+ T cell exhaustion represents a major hallmark of chronic HIV infection. Two key transcription factors governing CD8+ T cell differentiation, T-bet and Eomesodermin (Eomes), have previously been shown in mice to differentially regulate T cell exhaustion in part through direct modulation of PD-1. Here, we examined the relationship between these transcription factors and the expression of several inhibitory receptors (PD-1, CD160, and 2B4), functional characteristics and memory differentiation of CD8+ T cells in chronic and treated HIV infection. The expression of PD-1, CD160, and 2B4 on total CD8+ T cells was elevated in chronically infected individuals and highly associated with a T-betdimEomeshi expressional profile. Interestingly, both resting and activated HIV-specific CD8+ T cells in chronic infection were almost exclusively T-betdimEomeshi cells, while CMV-specific CD8+ T cells displayed a balanced expression pattern of T-bet and Eomes. The T-betdimEomeshi virus-specific CD8+ T cells did not show features of terminal differentiation, but rather a transitional memory phenotype with poor polyfunctional (effector) characteristics. The transitional and exhausted phenotype of HIV-specific CD8+ T cells was longitudinally related to persistent Eomes expression after antiretroviral therapy (ART) initiation. Strikingly, these characteristics remained stable up to 10 years after ART initiation. This study supports the concept that poor human viral-specific CD8+ T cell functionality is due to an inverse expression balance between T-bet and Eomes, which is not reversed despite long-term viral control through ART. These results aid to explain the inability of HIV-specific CD8+ T cells to control the viral replication post-ART cessation.
    Original languageEnglish
    Article numbere1004251
    JournalP L o S Pathogens
    Volume10
    Issue number7
    Number of pages15
    ISSN1553-7366
    DOIs
    Publication statusPublished - 2014

    Bibliographical note

    This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for
    any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

    Keywords

    • DNA and RNA Reverse Transcribing Viruses Viruses Microorganisms (DNA and RNA Reverse Transcribing Viruses, Microorganisms, Viruses) - Retroviridae [03305] HIV common Human immunodeficiency virus species pathogen
    • Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common adult, middle age host female, male
    • 2B4
    • CD160
    • Eomes expression
    • inhibitory receptors
    • PD-1
    • T-bet expression
    • transcription factors
    • 02506, Cytology - Animal
    • 02508, Cytology - Human
    • 10060, Biochemistry studies - General
    • 12512, Pathology - Therapy
    • 22002, Pharmacology - General
    • 22005, Pharmacology - Clinical pharmacology
    • 33502, Virology - General and methods
    • 34502, Immunology - General and methods
    • 34508, Immunology - Immunopathology, tissue immunology
    • 36006, Medical and clinical microbiology - Virology
    • Biochemistry and Molecular Biophysics
    • Clinical Immunology
    • Infection
    • Pharmacology
    • HIV infection human immunodeficiency virus infection viral disease, immune system disease drug therapy
    • viral replication
    • Human Medicine, Medical Sciences
    • CD8 positive T cell immune system
    • antiretroviral therapy ART therapeutic and prophylactic techniques, clinical techniques
    • MICROBIOLOGY
    • PARASITOLOGY
    • VIROLOGY
    • CHRONIC VIRAL-INFECTION
    • TRANSCRIPTION FACTOR EOMESODERMIN
    • HIGHLY PATHOGENIC SIV
    • C VIRUS-INFECTION
    • DISEASE PROGRESSION
    • PD-1 EXPRESSION
    • CUTTING EDGE
    • EFFECTOR FUNCTION
    • MEMORY
    • IMMUNE

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