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BRIEF REPORT | SEPTEMBER 15 2008
Cutting Edge: Programmed Death-1 Up-Regulation Is Involved in the
Attrition of Cytomegalovirus-Specic CD8
+
T Cells in Acute Self-Limited
Hepatitis B Virus Infection
1
Ji-Yuan Zhang; ... et. al
J Immunol (2008) 181 (6): 3741–3744.
https://doi.org/10.4049/jimmunol.181.6.3741
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Cutting Edge
Cutting Edge
Cutting Edge: Programmed Death-1 Up-Regulation Is
Involved in the Attrition of Cytomegalovirus-Specific
CD8
ⴙ
T Cells in Acute Self-Limited Hepatitis B
Virus Infection
1
Ji-Yuan Zhang,
2
Zheng Zhang,
2
Bo Jin, Shu-Ye Zhang, Chun-Bao Zhou,
Jun-Liang Fu, and Fu-Sheng Wang
3
Attrition of heterologous virus-specific CD8
ⴙ
T cells
has been demonstrated in murine viral infection; how-
ever, little is known regarding this phenomenon in hu-
man viral infections. In this study, we observed that
CMV-specific CD8
ⴙ
T cells displayed numerical de-
cline and functional impairment in the early phase of
acute infection, whereas programmed death-1 (PD-1)
expression was significantly up-regulated by these
CMV-specific CD8
ⴙ
T cells. This early PD-1 up-regu-
lation was found to be closely associated with the in-
creased apoptotic sensitivity of CMV-specific CD8
ⴙ
T
cells. The in vitro addition of anti-PD-1 further en-
hanced the spontaneous apoptosis of CMV-specific
CD8
ⴙ
T cells; however, blockade of the PD-1-mediated
pathway with anti-PD-L1 significantly restored the
CMV-specific CD8
ⴙ
T cell proliferation and IFN-
␥
production. Thus, PD-1 plays a crucial role in the attri-
tion of CMV-specific CD8
ⴙ
T cells in acute hepatitis B
virus infection, which in turn, influences the preexisting
homeostatic virus-specific CD8
ⴙ
T cell pool. The
Journal of Immunology, 2008, 181: 3741–3744.
Memory T cells are capable of stable survival after the
resolution of a pathogenic infection, even in envi-
ronments lacking MHC Ags (1). However, the sta-
ble survival of memory CD8
⫹
T cells in mice can be disrupted
by subsequent heterologous viral or bacterial infections in
which the number of the majority of non-cross-reactive mem-
ory CD8
⫹
T cells decreases via cytokine-dependent mecha-
nisms (2–6). In mice, this phenomenon has been identified as
the attrition of memory CD8
⫹
T cells (7, 8). The following two
models have been proposed to explain this attrition: 1) the pas-
sive attrition model, which predicts that old memory T cells are
defeated by newly formed memory T cells while competing for
survival niches within the immune system; and 2) the active at-
trition model, which predicts that the preexisting memory cells
undergo direct apoptotic attrition (7–9). However, in humans
there is no report on the attrition of memory CD8
⫹
T cells, and
the mechanisms underlying such attrition remain to be
elucidated.
The interaction between programmed death-1 (PD-1)
4
and
its ligand PD-L1 has been reported to play a crucial role in in-
ducing T cell exhaustion (10, 11), anergy (12), and apoptosis
(13) in mice and human viral infections (14 –22). These studies
indicated that PD-1 up-regulation may exhaust virus-specific
CD8
⫹
T cells, facilitating viral persistence in chronic viral in-
fection. The in vitro blockade of PD-1/PD-L1 interaction re-
versed the exhaustion of the virus-specific T cells (10–12, 14 –
19). In acute viral infections, PD-1 was transiently up-regulated
on virus-specific CD8
⫹
T cells in the early phase of the infec-
tion, and successful clearance of these viruses often correlated
with decreased PD-1 expression and the development of func-
tional CD8
⫹
memory T cells (21, 22). Moreover, PD-1-posi-
tive virus-specific CD8
⫹
T cells showed higher sensitivity to
apoptosis in the case of HIV-1 infection (15), and higher in
vitro PD-1/PD-L1 interaction enhanced the apoptosis of hep-
atitis B virus (HBV)-specific CD8
⫹
T cells during acute HBV
(AHB) infection (21). These findings indicate that PD-1-me-
diated coinhibitory signaling not only inhibits the function but
also regulates the survival of virus-specific CD8
⫹
T cells during
acute and chronic viral infections. Thus far, little information is
available regarding the roles of PD-1 in the attrition of heter-
ogenous virus-specific CD8
⫹
T cells. Notably, a recent study
demonstrated that PD-1 is responsible for the depletion of au-
toreactive CD8
⫹
T cells in mice (13).
In this study, we investigated the association between PD-1
expression and the fate of CMV-specific CD8
⫹
T cells in acute
Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China
Received for publication April 28, 2008. Accepted for publication July 24, 2008.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
1
This study was supported by National Key Basic Research Program of China Grants
2007CB512805 and 2006CB504305 and National Science Fund for Distinguished
Young Scholars Grant 30525042.
2
J.-Y.Z. and Z.Z. contributed equally to this work.
3
Address correspondence and reprint requests to Dr. Fu-Sheng Wang, Research Center
for Biological Therapy, Beijing 302 Hospital, Beijing 100039, China. E-mail address:
fswang@public.bta.net.cn
4
Abbreviations used in this paper: PD-1, programmed death-1; AHB, acute hepatitis B;
HBV, hepatitis B virus; HC, healthy control; HBsAg, hepatitis B surface antigen; PD-L1,
PD-1 ligand.
Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00
www.jimmunol.org
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self-limited HBV infection. HBV infection often results in
acute self-limited infection in adults with prominent clinical
presentation (20). The majority of the patients in this study had
previously been infected with CMV during early childhood and
established long-term immune protection against this infec-
tion. Our data indicate that PD-1 is involved in the attrition of
CMV-specific CD8
⫹
T cells in AHB, which, in turn, influ-
ences the preexisting homeostatic virus-specific CD8
⫹
T cell
pool.
Materials and Methods
Subjects
A total of 16 HLA-A2-positive AHB patients (12 male and four female; mean
age, 35.6 ⫾8.8 years) were diagnosed as described in our recent report (21). In
brief, the serum alanine aminotransferase levels at the clinical onset were at least
10-fold the upper limit of the normal level at the time of the first detection of
serum hepatitis B surface Ag (HBsAg) and Ig M anti-hepatitis B core Ag ac-
companying multispecific anti-HBV CD8
⫹
T cell responses (21). All of the
AHB patients finally recovered clinically and displayed alanine aminotransfer-
ase normalization and HBsAg seroconversion within 6 mo of the initial onset of
symptoms. Sixteen healthy subjects were recruited as controls (HCs). All par-
ticipants were anti-hepatitis A virus, anti-hepatitis C virus, anti-hepatitis D vi-
rus, and anti-HIV-1 and anti-HIV-2 Ab-negative. Informed consent was ob-
tained from each participant. The study was approved and has been reviewed by
the local medical ethics committee.
Abs and reagents
All Abs were purchased from BD Biosciences, except for the anti-
PD-L1-blocking mAb (MIH1) and the anti-human PD-1 Ab (AF 1086), which
were purchased from eBioscience and R&D Systems, respectively. A PE-labeled
CMV pentamer loaded with the pp65 epitope (495–503, NLVPMVATV) was
synthesized by ProImmune. Lymphocyte counts of these patients were deter-
mined using an automated differential blood count system. Plasma IFN-
␣
con-
centration was measured using a standard ELISA kit from BioSource
International.
Apoptosis assay
Freshly isolated PBMCs were stained with the PE-labeled CMV pentamer, fol-
lowed by anti-CD8-PerCP and anti-PD-1-allophycocyanin and finally with
annexin V according to our previously reported protocols (21). In some exper-
iments, 1–1.5 ⫻10
6
PBMCs were cultured in 24-well plates with or without
plate-bound anti-human PD-1 Ab (20
g/ml) for 12 h at 37°C. The cells were
subsequently stained with annexin V to detect apoptosis.
Intracellular IFN-
␥
staining assay
PBMCs were stimulated with pp65 495–504 peptide (10
g/ml) plus anti-
PD-L1 (10
g/ml) or isotype control Ab for 6 h. GolgiStop (BD PharMingen)
was added to the cells after stimulation for 2 h. Intracellular IFN-
␥
staining
assay was performed according to our previously reported protocols (16, 21).
Ag-specific cell proliferation
CFSE-based proliferation assays were performed according to our previously
described protocols (16, 21). Cells were stimulated with pp65 495–504 peptide
(2
g/ml), anti-human CD28 (0.5
g/ml), and human rIL-2 (20 U/ml) in the
presence of anti-PD-L1 (10
g/ml) or isotype control Ab in a 24-well plate. On
day 6, the cells were supplemented with 0.2 ml of fresh medium containing the
above-mentioned cytokines. On day 10, the cells were stained with pentamers.
Statistical analysis
All data were analyzed using SPSS software. Comparison between various
groups was performed using the Mann-Whitney Utest. For the blockade assay,
statistical comparisons were performed using the Wilcoxon matched pairs ttest.
The correlation between variables was evaluated using the Spearman’s rank cor-
relation test. For all two-tailed tests, p⬍0.05 was considered significant.
Results and Discussion
The attrition of preexisting virus-specific CD8
⫹
T cells follow-
ing heterologous viral infections has been well demonstrated in
mice models (2–9). However, whether this attrition occurs in
human viral infections is debatable; in particular, it is unknown
whether acute HBV infection affects the preexisting CMV-spe-
cific CD8
⫹
T cell pools in AHB patients. To address the issue,
we first found that both the percentages and absolute number of
CMV-specific CD8
⫹
T cells were significantly reduced at the
clinical onset of AHB in patients compared with those of HCs
(Fig. 1A). In contrast, multispecific anti-HBV CD8
⫹
T cell re-
sponses at such an early phase were observed in the patients
(21). Thus, these data primarily indicate that acute HBV infec-
tion may induce the attrition of CMV-specific CD8
⫹
T cells
during the early stage of HBV infection in humans. This early
attrition of CMV-specific CD8
⫹
T cells might make room for
newly formed HBV-specific T cells within the immune system
and facilitate the mounting of a strong anti-HBV T cell
response.
PD-1 has been demonstrated to regulate the survival of virus-
specific CD8
⫹
T cells during acute and chronic viral infections
(15, 21). To investigate the association between PD-1 expres-
sion and the attrition of CMV-specific CD8 T cells in AHB
infections, we serially analyzed the PD-1 expression on these
CMV-specific CD8 T cells. Our data indicated that PD-1 ex-
pression on CMV-specific CD8
⫹
T cells was significantly up-
regulated in AHB patients compared with that in HCs (Fig.
1B). The pool data further confirmed this observation (Fig.
1C). The underlying mechanism of PD-1 up-regulation on
these preexisting virus-specific CD8
⫹
T cells is not yet clear. A
study has suggested that PD-1 expression occurs before the ap-
pearance of early T cell activation markers, including CD69
and CD25, and that PD-1 expression may be controlled by
early responding cytokines in addition to TCR signaling (12).
In this regard, CMV was not observed to be reactivated, and no
cross-reactivity was observed between CMV and HBV in these
AHB patients. Interestingly, we found that PD-1 was also up-
regulated by influenza-specific CD8
⫹
T cells in AHB patients
FIGURE 1. Attrition of CMV-specific CD8
⫹
T cells at the clinical onset of
acute HBV infection. A, The percentages and numbers of CMV-pp65 CD8
⫹
T
cells in AHB patients and HCs. The numbers of circulating CMV-pp65 CD8
⫹
T cells were calculated as the lymphocyte count (cells/microliter) ⫻percentage
of CD8 ⫻percentage of CMV-pp65 pentamer. B, Representative dot plots of
PD-1 expression on CMV-pp65 CD8
⫹
T cells. Values in the upper right quad-
rants indicate the percentages of CMV-pp65 CD8
⫹
T cells that express PD-1.
C, Pool data of PD-1 expression on CMV-pp65 CD8
⫹
T cells. D, Pool data of
the plasma IFN-
␣
concentration.
3742 CUTTING EDGE: PD-1-MEDIATED MEMORY CD8 T CELL ATTRITION
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compared with those of HCs (data not shown). Thus, PD-1
up-regulation on CMV-specific CD8 T cells seems to be less
likely due to CMV-specific TCR signaling, provided that influ-
enza infection does not result in a viral persistence. Therefore,
further studies on the factors inducing PD-1 up-regulation on
CMV-specific CD8 T cells are warranted.
Notably, there is a difference in the time at which the re-
sponses were observed in the AHB patients of this study and in
the study performed on mice models. The IFN-induced attri-
tion observed in mice models occurred at the first few days of
infection before Ag-specific T cells in response to the acute in-
fection; this attrition can be easily detected (2–9). By contrast,
AHB patients are usually identified between 10 and 15 wk after
HBV infection, when they become clinically symptomatic;
HBV-specific T cells are detectable at this stage (21). Thus, al-
though we also found that the serum IFN-
␣
level was signifi-
cantly higher at clinical onset of infection than that in healthy
subjects (Fig. 1D), this time difference suggested that the attri-
tion of CMV-specific CD8 T cells in AHB patients may be a
different phenomenon than the IFN-induced attrition ob-
served in mice. Future studies should elucidate the mechanisms
responsible for the attrition in AHB patients.
PD-1 was originally cloned from apoptotic cell lines (22)
and could increase the apoptotic sensitivity of HBV-specific
CD8 T cells in acute HBV infections (21). Subsequently, we
examined whether PD-1 up-regulation affects the numbers
of CMV-specific CD8
⫹
T cells in AHB patients. Both PD-
1
high
and PD-1
median
CMV-specific CD8
⫹
T cell subsets
were observed to possess higher levels of annexin V staining
than the PD-1
low
subsets (Fig. 2A), suggesting that the
higher levels of PD-1 expression were associated with the
greater apoptosis sensitivity of CMV-specific CD8
⫹
T cells.
More importantly, we observed that plate-bound stimula-
tory anti-PD-1 directly enhanced the apoptosis of CMV-
specific CD8
⫹
T cells. Pooled data confirmed that the re-
sults were consistent for seven of nine patients (Fig. 2B). We
also longitudinally analyzed the association between PD-1
expression and the depletion of CMV-specific CD8
⫹
T cells
in seven AHB patients and found that the decreases in CMV-
specific CD8
⫹
T cells was positively correlated with the re-
duction in PD-1-expressing CMV-specific CD8
⫹
T cells
(Fig. 2C). These results indicate that PD-1 up-regulation
might mediate the apoptosis of CMV-specific CD8
⫹
T cells
in acute HBV infections.
FIGURE 2. PD-1 up-regulation is associated with the apoptosis of CMV-specific CD8
⫹
T cells in AHB patients. A, Representative histograms depict the annex-
in V positivity in PD-1
high
, PD-1
median
, and PD-1
low
CMV-pp65 CD8
⫹
T cells at the clinical onset in an AHB patient. Pool data indicate the percentages of annexin
V-positive cells in different subsets of CMV-pp65 CD8
⫹
T cell populations of 10 AHB patients. Horizontal bars present the median percentages of annexin
V-positive cells. B, Representative dot plots of annexin V staining in CMV-pp65 CD8
⫹
T cells in the presence and absence of plate-bound anti-PD-1 Ab (aPD-1).
Values in the upper right quadrants indicate the percentages of annexin V-positive CMV-pp65 CD8
⫹
T cells. The fold change in the percentage of CMV-pp65 CD8
⫹
T cells is shown. C, Representative dot plots represent the kinetics of PD-1 expression on CMV-pp65 CD8
⫹
T cells in acute HBV infections. The correlation
between the decrease in CMV-pp65 CD8
⫹
T cells and the reduction in PD-1-positive CMV-pp65 CD8
⫹
T cells was analyzed. Pen, Pentamer.
3743The Journal of Immunology
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Persistent PD-1 up-regulation can exhaust virus-specific T
cells during established chronic HIV, hepatitis C virus, and
HBV infections (10–19). In this section, we further
investigated whether the interference of PD-1 with PD-L1 in-
fluenced the function of CMV-specific CD8
⫹
T cells following
stimulation with a cognate peptide. We found that blockade of
PD-1/PD-L1 interaction by using an anti-PD-L1 blocking Ab
significantly increased IFN-
␥
production (Fig. 3, Aand C) and
the accumulation of CFSE
low
pentamers (Fig. 3, Band D)
among these CMV-specific CD8
⫹
T cells. However, due to the
high apoptotic sensitivity of the PD-1
high
CMV-specific CD8
⫹
T cells, this expansion of CMV-specific CD8
⫹
T cells in the
presence of anti-PD-L1 may be a direct result of enhanced
CD8
⫹
T cell proliferation, decreased apoptosis, or a combina-
tion of the two effects. These data indicated that PD-1 may also
participate in the functional attrition of CMV-specific CD8
⫹
T
cells in acute HBV infections.
In summary, this study provides the first indication that
PD-1 up-regulation, at least in part, contributes to the attrition
of CMV-specific CD8
⫹
T cells in acute HBV infections. These
findings, therefore, extended the attrition of memory T cells
from mouse viral infections to human viral infections and pre-
sented a mechanism that influences the homeostasis in the pre-
existing virus-specific CD8
⫹
T cell pool.
Acknowledgments
All authors express sincere thanks to all HBV-infected individuals and healthy
participants in this study.
Disclosures
The authors have no financial conflict of interest.
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FIGURE 3. PD-1 up-regulation impairs the function of CMV-specific
CD8
⫹
T cells in the early phase of acute HBV infection. A, Representative dot
plots represent the intracellular IFN-
␥
staining of CMV-pp65 CD8
⫹
T cells in
an AHB patient at the clinical onset. Values in the upper right quadrants indicate
the percentages of IFN-
␥
-producing CD8
⫹
T cells. B, Representative dot plots
represent CFSE staining in an AHB patient. Values in the upper left quadrant
indicate the percentage of CFSE
low
pentamers. (C) Summary data for the fold
change in the percentage of IFN-
␥
-producing CMV-pp65 CD8
⫹
T cells are
shown. D, Summary data for the fold change in the percentage of CFSE
low
pentamers are shown. Horizontal bars in Cand Dindicate the median fold
changes. aPD-11, anti-PD-11; Pen, pentamer.
3744 CUTTING EDGE: PD-1-MEDIATED MEMORY CD8 T CELL ATTRITION
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