Monitoring CD27 Expression to Evaluate Mycobacterium
Tuberculosis Activity in HIV-1 Infected Individuals In Vivo
Alexandra Schuetz1*¤, Antelmo Haule1, Klaus Reither1,2, Njabulo Ngwenyama3, Andrea Rachow1,2,
Andreas Meyerhans4, Leonard Maboko1, Richard A. Koup3, Michael Hoelscher2, Christof Geldmacher2,3
1NIMR-Mbeya Medical Research Programme, Referral Hospital, Mbeya, Tanzania, 2Department of Infectious Diseases and Tropical Medicine, Klinikum of University of
Munich, Munich, Germany, 3Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health,
Bethesda, Maryland, United States of America, 4Institute of Infections Medicine, Institute of Virology, Saarland University, Homburg/Saar, Germany
The level of bacterial activity is only poorly defined during asymptomatic Mycobacterium tuberculosis (MTB) infection. The
objective was to study the capacity of a new biomarker, the expression of the T cell maturation marker CD27 on MTB-
specific CD4 T cells, to identify active tuberculosis (TB) disease in subjects from a MTB and HIV endemic region. The
frequency and CD27 expression of circulating MTB-specific CD4 T cells was determined in 96 study participants after
stimulation with purified protein derivative (PPD) using intracellular cytokine staining for IFNgamma (IFNc). Subjects were
then stratified by their TB and HIV status. Within PPD responders, a CD272phenotype was associated with active TB in HIV2
(p=0.0003) and HIV+(p=0.057) subjects, respectively. In addition, loss of CD27 expression preceded development of active
TB in one HIV seroconverter. Interestingly, in contrast to HIV2subjects, MTB-specific CD4 T cell populations from HIV+TB-
asymptomatic subjects were often dominated by CD272cells. These data indicate that down-regulation of CD27 on MTB-
specific CD4 T cell could be used as a biomarker of active TB, potentially preceding clinical TB disease. Furthermore, these
data are consistent with the hypothesis that late, chronic HIV infection is frequently associated with increased mycobacterial
activity in vivo. The analysis of T cell maturation and activation markers might thus be a useful tool to monitor TB disease
Citation: Schuetz A, Haule A, Reither K, Ngwenyama N, Rachow A, et al. (2011) Monitoring CD27 Expression to Evaluate Mycobacterium Tuberculosis Activity in
HIV-1 Infected Individuals In Vivo. PLoS ONE 6(11): e27284. doi:10.1371/journal.pone.0027284
Editor: Ben J. Marais, University of Stellenbosch, South Africa
Received May 11, 2011; Accepted October 13, 2011; Published November 7, 2011
Copyright: ? 2011 Schuetz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The work was supported by grants from the European Commission (DG XII, INCO-DC, ERBICA4-CT-2002-10035 and DG X, EuropeAID SANTE/2004/078-
545/130). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: firstname.lastname@example.org
¤ Current address: Henry M. Jackson Foundation for the Advancement of Military Medicine, Walter Reed Program, Department of Retrovirology, USAMC-AFRIMS,
Tuberculosis (TB) is amongst the most frequent causes of death
from infection in humans, accounting for an estimated 1.8 million
deaths annually (WHO TB Factsheet, 2009) and frequently affects
immunocompromised patients co-infected with the human
immunodeficiency virus-1 (HIV). In MTB endemic regions, up
to 50% of HIV-infected individuals will eventually develop active
TB in the absence of antiretroviral therapy . In HIV-infected
subjects, TB progresses rapidly and is characterized by a high
mortality if left untreated . It is commonly assumed that in
HIV-infected individuals active TB is frequently caused by
reactivation of a latent MTB infection with an increased MTB
activity during chronic HIV-infection.
Diagnosis of active TB is usually based on characteristic X-ray
findings, clinical symptoms, tuberculin skin test (TST) and positive
sputum-smear microscopy or culture results. In HIV-infected
patients TB diagnosis is hampered by lower bacillary load in
sputum  during pulmonary TB and reduced delayed type
hypersensitive reactions during the TST . Interferon-gamma
(IFNc) release assays (IGRAs), which detect and quantify MTB-
specific cellular immune responses can improve diagnosis of MTB
infection . However, IGRAs do not discriminate between
‘‘latent’’ MTB infections (LTBI) and active TB. Furthermore, the
clinical term ‘‘latency’’ might indeed cover a spectrum of
manifestations ranging from complete elimination of MTB to
continuous low level replication in the absence of clinical TB
disease . Hence, there is no reliable test to rapidly diagnose and
monitor MTB activity in patients at high risk of developing clinical
disease such as HIV-infected patients or children.
MTB is largely controlled by cell-mediated immune responses.
Particularly CD4 T cells, which are gradually lost during HIV
infection, are thought to play a central role in controlling MTB
infection , and indeed MTB-specific CD4 T cells are depleted
relatively early in subjects who become HIV infected .
Maturation of pathogen-specific CD4 T cells is associated with
changes in the expression pattern of cell surface proteins, such as
CD27. CD27, a receptor involved in co-stimulation, is expressed on
thesurfaceofCD4T cellsandisdown regulatedwithadvancingcell
differentiation from early differentiated CD27+memory T cells to
late differentiated CD272memory T cells. Early differentiated
CD27+memory CD4 T cells are thought to mainly re-circulate
within the secondary lymphoid organs, whereas CD272late
differentiated memory T cells exhibit additional effector functions
and preferentially migrate into peripheral sites of inflammation,
such as the lung during active TB disease .
PLoS ONE | www.plosone.org1 November 2011 | Volume 6 | Issue 11 | e27284
Recently published data suggests that flow-cytometric analysis
of CD27 expression on circulating MTB-specific T cells can help
to discriminate active TB from LTBI . The present study
expands upon these findings and investigates CD27 expression on
MTB-specific CD4 T cell in relation to HIV and TB status within
a large cohort from Tanzania, a MTB and HIV high endemic
region. Our results indicated that monitoring CD27 expression on
MTB-specific CD4 T cells could be used as a biomarker of active
TB in HIV2and HIV+subjects, potentially proceeding active TB.
Furthermore the results support the hypothesis that late, chronic
HIV infection is frequently associated with increased mycobacte-
rial activity even in TB asymptomatic subjects.
Materials and Methods
A cross-sectional analysis of CD27 expression on PPD-specific
CD4T cellswasconductedina cohortof96 studyparticipantsfrom
the Mbeya Region, Southwest Tanzania. The study was approved
by the Mbeya Ethics and Research Committee, Tanzania, and the
National Ethical Committee/Medical Research Coordinating
Committee, National Institute for Medical Research, Tanzania.
TB disease included clinical assessment, chest X-ray, white blood
cell count, 26TB staining (Ziehl-Neelsen) of sputum, and 26TB
liquid culture (MGIT). Active TB or symptomatic TB was defined
by the presence of acid-fast bacilli in at least one out of two smear
sputum samples after Ziehl-Neelsen staining and identification of
MTB in BACTEC MGIT 960 (Becton Dickinson, Sparks, USA)
liquid culture isolates using the GenoTypeH test system (Hain
Lifescience, Nehren, Germany). Chest X-ray was routinely done in
all TB suspects. Participants were classified as TB asymptomatic
(TB2) when they did not show any symptoms suggestive of
pulmonary TB and when no acid-fast bacilli were detected in two
sputum samples by microscopy and liquid culture. Symptoms
suggesting active TB were defined as persistent cough for more than
unexplained weight loss and loss of appetite.
HIV-1 status was determined using repeated positive results on
enzyme immunoassay and Western blotting. Subsequently partic-
ipants were divided into 4 groups according to their TB and HIV
status (Table 1). HIV2(n=10) and HIV+antiretroviral therapy
(ART) naive patients (n=18) with confirmed active TB (active
TB), and HIV2(n=32) and HIV+(n=36) volunteers without any
symptoms suggestive of active TB disease (TB2) were included in
this study. 26 subjects had a viral load ,400 RNA copies/ml.
HIV+/TB2volunteers were recruited at the Mbeya Referral
Hospital HIV/AIDS care and treatment clinics and included 25
subjects on ART. Patients with active TB disease were recruited in
collaboration between the Mbeya Regional TB and Leprosy
Programme and the Mbeya Medical Research Programme
(MMRP) and subsequently received TB treatment. Additionally
two HIV seroconverters with positive PPD-responses from the
previously described HISIS cohort were included for longitudinal
analysis of CD27 expression .
For the cross-sectional study, the frequency and phenotype of
MTB-specific CD4 T cells was determined by intracellular cytokine
staining for IFNc after 6 h stimulation of fresh whole blood with
10 mmg/ml Purified Protein Derivative (PPD, Serum Staten
Institute) at 37uC and 5% CO2 as previously described . The
following antibodies were used CD4-allophycocyanin (APC), IFNc-
fluorescein isothiocyanate (FITC) and CD27-phycoerythrin (PE, all
Becton Dickinson). At least 30,000 cells were acquired and analyzed
on a FACS Calibur (Becton Dickinson). The cut off for each
antibody was determined based on the corresponding isotype
control. The following corresponding isotype controls were used
IgG1-APC (mouse), IgG1-FITC (mouse) and IgG1-PE (mouse, all
Becton Dickinson). In brief, whole blood was stained following the
same procedure as the samples  using the corresponding isotype
control to determine the cut off for the negative and positive
populations. Figure 1A shows a representative staining for IFNc-
FITC and CD27-PE as well as their corresponding IgG1isotype
controls used to determine the cut off.
Initial gating for each sample set used a forward scatter height
(SSC-H) versus a sideward scatter height (SSC-H) plot to isolate
small lymphocytes. CD4 versus IFNc plot was then used to
identify MTB-specific CD4 T cell responses. Definition of positive
CD4 T cell responses was 3-times background and at least 0.05%
IFNc positive after subtraction of the background. As shown in
figure 1B, CD27 positive and CD27 negative CD4 T cells were
clearly separate according to their isotype control staining (shown
in figure 1A). As negative and positive controls, whole blood was
stimulated with PPD diluent and Staphylococcus aureus Enterotoxin B
(SEB, Sigma), respectively. Figure 1C shows a representative dot
plot of a negative and positive control used for each sample.
Subjects without a detectable response to SEB (n=6) or with a
high background were excluded (n=4).
Frozen peripheral blood mononuclear cells (PBMC) from
multiple time points of two HIV seroconverters with latent MTB
infection were used to study CD27 expression dynamics on MTB-
specific CD4 T cells. Latent MTB infection was defined as
detectable Region of Difference 1 (RD-1)-specific T cell responses
targeting Early Secretory Antigenic Target 6 (ESAT-6) and/or
Culture Filtrate Protein 10 (CFP-10). For these samples, flow
cytometric studies were performed at the Vaccine Research
Center, National Institutes of Health, Bethesda, USA, using a
Table 1. Group characteristics and immunological results of the 96 subjects enrolled in the cross-sectional study.
self-reported PPD responders
Ratio , ,1
32 NA119 (59%)41.4279%
10NA08 (80%)80.48 80%
35 259 14 (40%)9 0.92 75%
1800 16 (89%) 140.2778%
NA=not applicable; ART=antiretroviral treatment; PPD+CD27 Ratio=number of PPD-specific CD4 T cells positive for IFN gamma divided by the number of respective
CD272CD4 T cells.
*Diagnostic concordance MTB culture defines the proportion of concordant results defined by PPD response and CD27 expression of PPD-specific CD4 T cells.
Expression of CD27 to Monitor TB Activity
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previously described protocol . In brief, after stimulation,
PBMC were washed once with PBS and stained with Vivid
(Molecular Probes) , to exclude dead cells. Subsequently,
surface staining was performed with CD4-PE-Cy5.5 (Invitrogen),
and CD27 PE-Cy5 (Beckmann Coulter) for 20 min. PBMC were
then permeabilized using the Cytofix/Cytoperm kit (BD Biosci-
ences), after which they were stained for CD3 APC-Cy7 and IFNc
FITC (Becton Dickinson), besides other cytokines. PBMC were
then washed and fixed with 1% paraformaldehyde and analysis
was done using a modified LSR II flow cytometer (BD
Immunocytometry Systems). Between 300,000 and 1,000,000
total events were collected from each sample. Electronic
compensation was conducted with antibody capture beads (BD
Biosciences) stained separately with the individual antibodies while
the cut off definition described above were used.
Data analyses were carried out using GraphPad Prism version
4.0 software. Comparisons of two groups were performed using
the Mann Whitney test.
Figure 1. Characterization of CD27 expression on PPD-specific CD4 T cells in whole blood. (A) The cut off for CD27 expression was
determined based on the corresponding isotype control for each antibody. Shown is a representative staining for IFNc-FITC and CD27-PE as well as
their corresponding IgG1isotype controls that were used to determine the cut off. (B) Gating strategy to identify PPD-specific CD4 T cells and to
analyse the CD27 expression on IFNc-positive CD4 T cells after 6 h of PPD-stimulation during the cross-sectional study. (C) Representative staining for
negative and positive controls using PPD diluent and SEB, respectively, for stimulation.
Expression of CD27 to Monitor TB Activity
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Table 1 summarizes group characteristics and immunological
results of the cross-sectional analysis. 59% of TB2/HIV2subjects
(19/32) and 40% of TB2/HIV+subjects (14/35) had detectable
PPD-specific CD4 T cell responses (cut off: at least 0.05% IFNc+
CD4 T cells), consistent with previous results that HIV infection is
associated with a reduction of PPD-specific CD4 T cell responses
. As expected, active TB was associated with detectable PPD-
specific CD4 T cell responses; 80% of active TB/HIV2subjects
(8/10) and 89% of active TB/HIV+subjects (16/18) had
detectable PPD-specific CD4 T cell responses.
Subsequently, the expression of CD27 on PPD-specific CD4 T
cells was analysed. In order to compare CD27 expression on PPD-
specific CD4 T cells between different PPD responders, the
fraction of CD27+IFNc+CD4 T cells was divided through the
Figure 2. Down regulation of CD27 on PPD-specific CD4 T cells is associated with active Tuberculosis independent of the HIV status
and with progression to active TB in a HIV+seroconverter. (A) Ratio of IFNc+CD4 T cells that are CD27+divided by those that are CD272is
shown for 4 different groups of PPD responders delineated by TB disease state and by HIV serology. CD4+T cells were analyzed for each sample using
a whole blood intracellular cytokine assay. (B) Histogram analysis of CD27 expression on IFNc+PPD-specific CD4 T cells (blue line) and total CD4 T
cells (black line, grey) over a 15 months period in two subjects who became HIV infected. Subject H19 (upper panel) was diagnosed and treated for
active TB 15 months after HIV infection. Subject H228 (lower panel) did not develop TB within three years after HIV infection. Longitudinal analysis
of CD27 expression for one subject was determined simultaneously by flow cytometry.
Expression of CD27 to Monitor TB Activity
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fraction of CD272IFNc+CD4 T cells as shown in figure 1B and
C. A ratio of .1 defines that a majority of PPD-specific CD4 T
cells is characterized by a CD27+phenotype, whereas a ratio ,1
defines that a majority of PPD-specific CD4 T cells have a CD272
phenotype. As shown in figure 2A 79% (15/19) of TB2/HIV2
PPD responders had a ratio .1 with a median ratio of 1.42 (range
0.52–12.29). Only 4 subjects (23%) had a ratio ,1. In contrast,
100% of active TB/HIV2subjects (8/8) with a PPD-specific T cell
response had a ratio #1 (p=0.0003). The median ratio within the
active TB/HIV2group was 0.48 (range 0.28–1.00). These results
demonstrate that active TB is associated with down regulation of
CD27 on PPD-specific CD4 T cells in the absence of HIV co-
infection. In active TB/HIV+subjects with detectable PPD
responses, 14/16 (88%) subjects had a ratio of ,1. The median
ratio was 0.27 (range 0.08–4.99) and was modestly decreased
compared to HIV2subjects with active TB (p-value=0.11). In
contrast to the TB2/HIV2group, 9/14 TB2/HIV+PPD-
responders (64%) had a ratio ,1 and a median ratio of 0.92
(range 0.0–15.94, Figure 2A). Thus in the presence of HIV
infection, CD27 down regulation on PPD-specific CD4 T cells was
observed not only in association with active TB, but also within the
majority of TB2/HIV+subjects. These results are consistent with
the hypothesis that chronic HIV infection is frequently associated
with low levels of MTB replication in subjects with sub-clinical
We then determined the longitudinal course of CD27
expression on MTB-specific CD4 T cells before and after
acquisition of HIV in two IGRA-positive seroconverters with
detectable PPD-responses throughout the study [11,14]. Subject
H19, was diagnosed with active TB at 15 month after HIV
seroconversion whereas subject H228 stayed TB-asymptomatic
despite significantly decreased frequencies of PPD-specific CD4 T
cells 12 month post HIV infection . As shown for subject H19
in figure 2B (upper panel), a substantial down regulation of CD27
on MTB-specific T cells was observed as early as 9 month before
active TB was diagnosed. The observed down regulation was
specific for MTB since total CD4 cells (grey) were not affected. In
contrast, expression of CD27 on MTB-specific CD4 T cells was
maintained in subject H228 (lower panel) throughout the study
period, while remaining TB-asymptomatic. These results suggest
that mycobacterial activity in subject H19 preceded clinical disease
for several months.
HIV related immunosuppression is associated with increased
susceptibility to severe, frequently extrapulmonary tuberculosis
. Here we present data suggesting that monitoring PPD-specific
T cell responses and their CD27 expression pattern can hold
important information about mycobacterial activity in vivo. In
subjects with active TB, MTB-specific CD4 T cells dominantly
exhibit a more mature CD272phenotype regardless of the HIV
status, whereas in HIV2TB asymptomatic PPD-responders,
MTB-specific CD4 T cells exhibit dominantly a less differentiated
CD27+phenotype. These data are in line with observations from a
low MTB endemic country and suggest that down regulation of
CD27 on MTB-specific CD4 T cells correlates with active MTB
growth . Likewise, recent studies in a TB mouse model showed
that more mature CD272CD4 T cells are found in the lungs of
infected animals and produce significant amounts of IFNc after
We have recently shown that MTB-specific CD4 T cell
populations are depleted early after HIV infection [8,14].
However, in many TB asymptomatic subjects with chronic HIV
infection these responses are still detectable. The significance of
such responses remains largely unknown but might be related to
recent exposure, not sufficiently controlled low levels of MTB
replication or reactivation that finally leads to clinical TB disease
. Interestingly, TB2subjects differed in this marker when
stratified by their HIV infection status. MTB-specific CD4 T cells
detected in TB2/HIV2subjects showed a less differentiated
CD27+phenotype, whereas in a majority of TB2/HIV+subjects,
the phenotype was dominantly CD272. The TB2/HIV+subjects
were recruited from a HIV/AIDS care and treatment clinic with
the majority on ART (table 1) and 9 subjects reported previous
episodes of TB disease, suggesting that most of these subjects were
in the late, chronic stage of HIV infection. Because re-expression
of CD27 on MTB-specific CD4 T cells has been shown to occur
very slowly upon TB treatment , these data are consistent with
the hypothesis that TB2/HIV+subjects with CD272MTB-
specific CD4 T cell responses, might have been exposed to
subclinical, low levels of MTB replication before commencing
ARV treatment. In deed, a follow up after 2 years did not reveal
any association of a CD272
reactivating Tuberculosis within HIV+subjects that had started
ART. Thus in HIV+subjects on ART the usability of this marker
to diagnose active TB might be limited.
Down regulation of CD27 on MTB-specific CD4 T cells
preceded the diagnosis of active TB for several months in one
individual who continuously mounted MTB-specific responses
despite recent HIV infection . In contrast CD27 down
regulation was not observed in the subject that stayed TB-
asymptomatic throughout the observation period suggesting that
HIV infection alone does not explain CD27 down regulation on
MTB-specific CD4 T cells. Although it is impossible to draw
definite conclusions from only 2 patients, this observation supports
the hypothesis that in HIV+subjects MTB growth can start long
before clinical disease. However, larger studies are needed to
corroborate the predictive value of this assay.
In conclusion we demonstrate that active TB is associated with
down regulation of CD27 on MTB-specific CD4 T cells in HIV2
subjects from a high TB endemic region. These data suggest that
phenotypic analysis of MTB-specific T cells could be used to assess
MTB activity in vivo, to assist the diagnosis of TB, and thus to
more accurately evaluate the risk of developing active TB.
phenotype with subsequent
We thank all the volunteers of the Mbeya Region, Southwest Tanzania
that participated in this study.
Conceived and designed the experiments: AS AM AH NN CG LM.
Performed the experiments: AS AH NN AR KR. Analyzed the data: AS
CG MH RAK KR. Contributed reagents/materials/analysis tools: RAK
MH. Wrote the paper: AS CG MH RAK KR.
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