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

doi:10.1371/journal.ppat.1004251

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-bet^dimEomes^hi expressional profile. Interestingly, both resting and activated HIV-specific CD8+ T cells in chronic infection were almost exclusively T-bet^dimEomes^hicells, while CMV-specific CD8+ T cells displayed a balanced expression pattern of T-bet and Eomes. The T-bet^dimEomes^hivirus-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 language	English
Article number	e1004251
Journal	P L o S Pathogens
Volume	10
Issue number	7
Number of pages	15
ISSN	1553-7366
DOIs	https://doi.org/10.1371/journal.ppat.1004251
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Buggert, M., Tauriainen, J., Yamamoto, T., Frederiksen, J. W., Ivarsson, M. A., Michaelsson, J., Lund, O., Hejdeman, B., Jansson, M., Sonnerborg, A., Koup, R. A., Betts, M. R., & Karlsson, A. C. (2014). T-bet and Eomes Are Differentially Linked to the Exhausted Phenotype of CD8+T Cells in HIV Infection. P L o S Pathogens, 10(7), Article e1004251. https://doi.org/10.1371/journal.ppat.1004251

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

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.",

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doi = "10.1371/journal.ppat.1004251",

language = "English",

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journal = "P L o S Pathogens",

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Buggert, M, Tauriainen, J, Yamamoto, T, Frederiksen, JW, Ivarsson, MA, Michaelsson, J, Lund, O, Hejdeman, B, Jansson, M, Sonnerborg, A, Koup, RA, Betts, MR & Karlsson, AC 2014, 'T-bet and Eomes Are Differentially Linked to the Exhausted Phenotype of CD8+T Cells in HIV Infection', P L o S Pathogens, vol. 10, no. 7, e1004251. https://doi.org/10.1371/journal.ppat.1004251

TY - JOUR

T1 - T-bet and Eomes Are Differentially Linked to the Exhausted Phenotype of CD8+T Cells in HIV Infection

AU - Buggert, Marcus

AU - Tauriainen, Johanna

AU - Yamamoto, Takuya

AU - Frederiksen, Juliet Wairimu

AU - Ivarsson, Martin A.

AU - Michaelsson, Jakob

AU - Lund, Ole

AU - Hejdeman, Bo

AU - Jansson, Marianne

AU - Sonnerborg, Anders

AU - Koup, Richard A.

AU - Betts, Michael R.

AU - Karlsson, Annika C.

N1 - 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.

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N2 - 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.

AB - 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.

KW - 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

KW - Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common adult, middle age host female, male

KW - 2B4

KW - CD160

KW - Eomes expression

KW - inhibitory receptors

KW - PD-1

KW - T-bet expression

KW - transcription factors

KW - 02506, Cytology - Animal

KW - 02508, Cytology - Human

KW - 10060, Biochemistry studies - General

KW - 12512, Pathology - Therapy

KW - 22002, Pharmacology - General

KW - 22005, Pharmacology - Clinical pharmacology

KW - 33502, Virology - General and methods

KW - 34502, Immunology - General and methods

KW - 34508, Immunology - Immunopathology, tissue immunology

KW - 36006, Medical and clinical microbiology - Virology

KW - Biochemistry and Molecular Biophysics

KW - Clinical Immunology

KW - Infection

KW - Pharmacology

KW - HIV infection human immunodeficiency virus infection viral disease, immune system disease drug therapy

KW - viral replication

KW - Human Medicine, Medical Sciences

KW - CD8 positive T cell immune system

KW - antiretroviral therapy ART therapeutic and prophylactic techniques, clinical techniques

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KW - PARASITOLOGY

KW - VIROLOGY

KW - CHRONIC VIRAL-INFECTION

KW - TRANSCRIPTION FACTOR EOMESODERMIN

KW - HIGHLY PATHOGENIC SIV

KW - C VIRUS-INFECTION

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KW - PD-1 EXPRESSION

KW - CUTTING EDGE

KW - EFFECTOR FUNCTION

KW - MEMORY

KW - IMMUNE

U2 - 10.1371/journal.ppat.1004251

DO - 10.1371/journal.ppat.1004251

M3 - Journal article

C2 - 25032686

SN - 1553-7366

VL - 10

JO - P L o S Pathogens

JF - P L o S Pathogens

IS - 7

M1 - e1004251

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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