Cutting Edge: Prolonged Exposure to HIV Reinforces a Poised Epigenetic Program for PD-1 Expression in Virus-Specific CD8 T Cells

Youngblood, Benjamin A.; Noto, Alessandra; Porichis, Filippos; Akondy, Rama; Ndhlovu, Zaza M.; Austin, James W.; Bordi, Rebeka; Procopio, Francesco A.; Miura, Toshiyuki; Allen, Todd M.; Sidney, John; Sette, Alessandro; Walker, Bruce D.; Ahmed, Rafi; Boss, Jeremy M.; Sékaly, Rafick‐Pierre; Kaufmann, Daniel E.

doi:10.4049/jimmunol.1203161

Cited by 145 publications

(139 citation statements)

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“…We have recently reported that the PD-1 transcriptional regulatory region underwent dynamic change in epigenetic programming during the development of functional memory and exhausted CD8 T cells. Specifically, we observed that functional memory CD8 T cells reacquired a methylated PD-1 promoter while the PD-1 promoter remained unmethylated in exhausted CD8 T cells even when viral loads were reduced to undetectable levels (25,26). These reports suggest that long-term antigen exposure enforces the demethylation of the PD-1 promoter in fully exhausted CD8 T cells.…”

mentioning

confidence: 61%

“…Our previous study revealed that PD-1 expression on exhausted CD8 T cells was coupled to DNA demethylation of the PD-1 transcriptional regulatory region (25). Interestingly, exhausted CD8 T cells retained the unmethylated PD-1 loci even when the viral load was reduced to undetectable levels at the late phase of mouse and human chronic infection (25,26). This study generated several important questions: was the retained demethylated state simply due to the persistence of a low level of antigen exposure?…”

Section: Discussionmentioning

confidence: 98%

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Demethylation of the PD-1 Promoter Is Imprinted during the Effector Phase of CD8 T Cell Exhaustion

Ahn

Youngblood

Lee

et al. 2016

J Virol

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PD-1 is an inhibitory receptor that has a major role in T cell dysfunction during chronic infections and cancer. While demethylation of the PD-1 promoter DNA is observed in exhausted T cells isolated from chronically infected individuals, little is known about when this stable demethylation of PD-1 promoter DNA is programmed during the course of a chronic infection. To assess if PD-1 promoter DNA demethylation is impacted by prolonged stimulation during effector phase of chronic infection, we adoptively transferred virus-specific day 8 effector CD8 T cells from mice infected with lymphocytic choriomeningitis virus (LCMV) clone 13 into recipient mice that had cleared an acute infection. We observed that LCMV-specific CD8 T cells from chronically infected mice maintained their surface expression of PD-1 even after transfer into acute immune mice until day 45 posttransfer. Interestingly, the PD-1 transcriptional regulatory region continued to remain unmethylated in these donor CD8 T cells generated from a chronic infection. The observed maintenance of PD-1 surface expression and the demethylated PD-1 promoter were not a result of residual antigen in the recipient mice, because similar results were seen when chronic infection-induced effector cells were transferred into mice infected with a variant strain of LCMV (LCMV V35A) bearing a mutation in the cognate major histocompatibility complex class I (MHC-I) epitope that is recognized by the donor CD8 T cells. Importantly, the maintenance of PD-1 promoter demethylation in memory CD8 T cells was coupled with impaired clonal expansion and higher PD-1 re-expression upon secondary challenge. These data show that the imprinting of the epigenetic program of the inhibitory receptor PD-1 occurs during the effector phase of chronic viral infection. IMPORTANCESince PD-1 is a major inhibitory receptor regulating T cell dysfunction during chronic viral infection and cancers, a better understanding of the mechanisms that regulate PD-1 expression is important. In this work, we demonstrate that the PD-1 epigenetic program in antigen-specific CD8 T cells is fixed during the priming phase of chronic infection. CD8 T cells play a critical role in controlling acute viral infections and, upon control, can establish antigen-specific memory that provides the host with long-lived immunity to the previously experienced pathogen. While chronic pathogens also generate robust CD8 T cell responses, prolonged exposure to high levels of antigen results in the decline of CD8 T cell effector functions. The progressive decline of effector function in antigen-specific CD8 T cells is coupled with reduced proliferative potential and repression in the ability to express the cytokines interleukin 2 (IL-2), tumor necrosis factor alpha (TNF-␣), and gamma interferon (IFN-␥) upon antigenic restimulation (1, 2). This progressive decline in T cell effector function, known as T cell exhaustion, poses a major challenge for controlling chronic diseases, including HIV, hepatitis C virus (HCV), and HBV infec...

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confidence: 61%

Section: Discussionmentioning

confidence: 98%

Demethylation of the PD-1 Promoter Is Imprinted during the Effector Phase of CD8 T Cell Exhaustion

Ahn

Youngblood

Lee

et al. 2016

J Virol

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“…Thus, in agreement with previous reports (55, 56), we conclude that expansion in IL-2 alters the expression of these markers and compromises the potential use of inhibitory receptors to select for tumor-reactive cells after in vitro expansion. Recent work in animal models suggests that chronic antigen stimulation (57)(58)(59) or a tolerizing microenvironment (60) may lead to permanent epigenetic changes in T cells, raising the possibility that the restoration of function observed in previously exhausted or tolerized cells in presence of cytokines may only be transient. These results have not yet been corroborated in human tumor-specific cells.…”

Section: Discussionmentioning

confidence: 99%

PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors

Gros¹,

Robbins²,

Yao³

et al. 2014

J. Clin. Invest.

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Adoptive transfer of tumor-infiltrating lymphocytes (TILs) can mediate regression of metastatic melanoma; however, TILs are a heterogeneous population, and there are no effective markers to specifically identify and select the repertoire of tumor-reactive and mutation-specific CD8 + lymphocytes. The lack of biomarkers limits the ability to study these cells and develop strategies to enhance clinical efficacy and extend this therapy to other malignancies. Here, we evaluated unique phenotypic traits of CD8 + TILs and TCR β chain (TCRβ) clonotypic frequency in melanoma tumors to identify patient-specific repertoires of tumor-reactive CD8 + lymphocytes. In all 6 tumors studied, expression of the inhibitory receptors programmed cell death 1 (PD-1; also known as CD279), lymphocyte-activation gene 3 (LAG-3; also known as CD223), and T cell immunoglobulin and mucin domain 3 (TIM-3) on CD8 + TILs identified the autologous tumor-reactive repertoire, including mutated neoantigen-specific CD8 + lymphocytes, whereas only a fraction of the tumor-reactive population expressed the costimulatory receptor 4-1BB (also known as CD137). TCRβ deep sequencing revealed oligoclonal expansion of specific TCRβ clonotypes in CD8 + PD-1 + compared with CD8 + PD-1 -TIL populations. Furthermore, the most highly expanded TCRβ clonotypes in the CD8 + and the CD8 + PD-1 + populations recognized the autologous tumor and included clonotypes targeting mutated antigens. Thus, in addition to the well-documented negative regulatory role of PD-1 in T cells, our findings demonstrate that PD-1 expression on CD8 + TILs also accurately identifies the repertoire of clonally expanded tumor-reactive cells and reveal a dual importance of PD-1 expression in the tumor microenvironment.

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“…The de-methylation was maintained in antigen-specific T-cells long after LCMV clone-13 virus load has dropped below detectable levels in the blood 65 . A lack of methylation in the PD-1 promoter region has also been observed among antigen-specific CD8 T-cells from HIV patients which have been treated long-term (>2 years) with anti-retroviral therapy or in elite controllers 66 What remains unknown, however, is when T-cells undergo this differentiation. The incremental appearance of T-cells with an "exhausted" phenotype led to the conclusion that prolonged exposure to antigen and inflammation causes a progressively occurring acquisition of an exhausted phenotype 68 .…”

Section: T-cells Undergo Stable Differentiation In Persisting Infectimentioning

confidence: 99%

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

et al. 2014

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Chronic viral infections and malignant tumours induce T cells that have a reduced ability to secrete effector cytokines and have upregulated expression of the inhibitory receptor PD1 (programmed cell death protein 1). These features have so far been considered to mark terminally differentiated 'exhausted' T cells. However, several recent clinical and experimental observations indicate that phenotypically exhausted T cells can still mediate a crucial level of pathogen or tumour control. In this Opinion article, we propose that the exhausted phenotype results from a differentiation process in which T cells stably adjust their effector capacity to the needs of chronic infection. We argue that this phenotype is optimized to cause minimal tissue damage while still mediating a critical level of pathogen control. In contrast to the presently held view of functional exhaustion, this new concept better reflects the pathophysiology and clinical manifestations of persisting infections, and it provides a rationale for emerging therapies that enhance T cell activity in chronic infection and cancer by blocking inhibitory receptors. Daniel T. Utzschneider Division of Immunology and Allergy of the Lausanne University Hospital (CHUV) and Swiss Vaccine Research Institute (SVRI), Lausanne, SwitzerlandDaniel Utzschneider is a PhD student of Dietmar Zehn. His research is focused on T-cell differentiation in chronic infection. Susanne G. Oberle Division of Immunology and Allergy of the Lausanne University Hospital (CHUV) and Swiss Vaccine Research Institute (SVRI), Lausanne, SwitzerlandSusanne Oberle is a PhD student of Dietmar Zehn. Her research interests are focused on investigating T-cell responses in acute and chronic infections. and it provides a rational for emerging therapies that enhance T-cell activity in chronic infection and cancer by blocking inhibitory receptors. Christian Münz PhD

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Cutting Edge: Prolonged Exposure to HIV Reinforces a Poised Epigenetic Program for PD-1 Expression in Virus-Specific CD8 T Cells

Cited by 145 publications

References 32 publications

Demethylation of the PD-1 Promoter Is Imprinted during the Effector Phase of CD8 T Cell Exhaustion

Demethylation of the PD-1 Promoter Is Imprinted during the Effector Phase of CD8 T Cell Exhaustion

PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

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