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Prepublished online as a Blood First Edition Paper on October 17, 2002; DOI 10.1182/blood-2002-09-2681.
IMMUNOBIOLOGY
From the Institut de Génétique
Moléculaire de Montpellier, CNRS UMR 5535/IFR 24, F-34293
Montpellier Cedex 5, France.
The human T-cell leukemia virus type 1 (HTLV) is the first
isolated human retrovirus, but its receptor has yet to be identified, in part due to its ubiquitous expression. Here we report that quiescent
CD4 and CD8 T lymphocytes do not express this receptor, as monitored
with a soluble receptor-binding domain derived from the HTLV envelope.
However, HTLV receptor is an early activation marker in neonatal and
adult T lymphocytes, detected as early as 4 hours following
T-cell-receptor (TCR) stimulation. This induced surface expression of
the HTLV receptor requires de novo protein synthesis and results in a
wide distribution on the surface of activated lymphocytes. Moreover,
the distribution of the HTLV receptor is independent of TCR/CD3-capped
membrane structures, as observed by confocal immunofluorescence
microscopy. To determine whether HTLV receptor up-regulation
specifically requires TCR-mediated signals or, alternatively, is
dependent on more generalized cell cycle entry/proliferation signals,
its expression was monitored in interleukin 7 (IL-7)-stimulated
neonatal and adult T cells. Neonatal, but not adult, lymphocytes
proliferate in response to IL-7 and HTLV receptor expression is
restricted to the former population. Thus, HTLV receptor expression
appears to be an early marker of cell cycle entry. Up-regulation of the
HTLV receptor, via signals transmitted through the IL-7 cytokine
receptor as well as the TCR, is likely to contribute to the
mother-to-infant transmission and spreading of HTLV-1.
(Blood. 2003;101:1913-1918) The human T-cell leukemia virus type 1 (HTLV-1),
the first characterized human retrovirus,1 is present in
all areas of the world as either an endemic or a sporadic infectious
agent.2 In endemic areas, HTLV-1 transmission seems to
occur mostly from mother to infant through
breast-feeding.3 The exceptionally broad tropism of HTLV-1
in vitro4,5 contrasts with the finding that in vivo,
HTLV-1 is found primarily in CD4+ lymphocytes and less
frequently in other mononuclear blood cells.6,7 Studies of
this apparent discrepancy have been hindered by the high cytotoxicity
of HTLV envelopes and their dependence on cell-to-cell contact for
infection and spreading.4,8,9 Moreover, investigations have been limited because the HTLV envelope receptor remains
unidentified, even though multiple cell surface components including
adhesion molecules,10,11 matrix-associated
proteins,12 lipids,13 and lipid
rafts,14 have been implicated in HTLV envelope
(Env)-mediated membrane fusion and virus transmission.
The HTLV-1 Env receptor-binding determinants are entirely
contained within the extracellular surface component
(SU).4,15 Recently, we demonstrated that the
amino-terminal 215 amino acids of the SU harbors the receptor-binding
domain (RBD) of HTLV Env.16 The binding specificity
of a soluble tagged construct encompassing this region
(HRBD) has been demonstrated by its efficient competition with HTLV Env-mediated cell fusion and infection (F.J.K., E. N. Garrido, N.M., M.S., J.-L.B., manuscript in preparation).
Using the RBD of HTLV Env, we have now tracked HTLV receptor expression
on T lymphocytes, which have been reported to be a major HTLV-1
reservoir in vivo. Circulating T lymphocytes are almost entirely in the
G0 phase of the cell cycle. Activation of these cells via
their cognate antigen receptor is the predominant feature of an
efficient immune response. On activation, expression of numerous
surface markers is modulated,17,18 cytokines are secreted,
and cells can undergo as many as 6 to 8 divisions. Here, we have
assessed whether expression of the HTLV receptor on T lymphocytes is
modulated by their activation state. Although it has previously not
been possible to identify mammalian cell types that do not express the
HTLV receptor,4,15 we now report that quiescent T
lymphocytes do not express the HTLV receptor. Rather, receptor
expression on T lymphocytes is induced by T-cell-receptor (TCR)
engagement and requires de novo protein synthesis. Furthermore, interleukin 7 (IL-7)-stimulated neonatal and adult T lymphocytes demonstrate distinct cell surface HTLV receptor levels,
with significantly higher expression in the immature neonatal
T-cell population.
Generation of HTLV and amphotropic MLV Env fusion
proteins
HRBD, ARBD, and HRBD-EGFP proteins
were produced by transfecting 293 T cells with the appropriate
constructs or with the empty control vector using the calcium phosphate
method. After transfection, cells were washed twice with
phosphate-buffered saline (PBS) and fresh medium was added. Media
containing the various soluble RBDs were harvested 1 day later and
clarified by a 5-minute centrifugation at 13 000 rpm at 4°C.
Cell isolations and culture conditions
The Jurkat T-cell clone 77-6.8, generously provided by Dr K. A. Smith (New York, NY), was maintained in RPMI 1640 medium supplemented with 10% FCS. Flow cytometry for Env binding, surface markers, and cell cycle analysis To evaluate binding of HRBD and ARBD experiments, 5 × 105 CD4+ T cells were washed with PBA (PBS containing 1% bovine serum albumin [BSA] and 0.1% sodium azide), incubated with 0.3 mL control, HRBD, or ARBD supernatants for 30 minutes at room temperature, washed, and labeled for 20 minutes on ice with an FITC-conjugated sheep anti-rFc antibody (1:500 dilution; Sigma). To detect expression of CD4, CD8, CD25, CD69, CD45RA, and CD45RO, cells were incubated for 20 minutes on ice with the appropriate PE-conjugated mAbs or PE-conjugated isotype control mAbs (Immunotech). In all cases, cells were immediately analyzed on a FACSCalibur (Becton Dickinson) and data analysis was performed using CellQuest software (Becton Dickinson).The percentage of cells in the S-G2/M phases of the cell cycle was determined by propidium iodide (PI) staining. At the indicated time point, cells were resuspended in PI (50 µg/mL) diluted in PBS with 5% glycerol and 0.1% Triton X-100 and incubated for 15 minutes prior to analysis. Cell cycle was analyzed on the FL2-A wavelength after gating out signals due to cell debris. Confocal immunofluorescence microscopy CD4+ T cells (5 × 105) were washed with PBS and incubated with HRBD-EGFP supernatants as well as either CD4 or CD3 mAbs (0.5 µg) for 30 minutes at
room temperature. Cells were then fixed with 3.7% paraformaldehyde in
PBS, washed with ice-cold PBS containing 0.1% BSA, and labeled with
Cy3-conjugated sheep mouse-IgG (1:500; Sigma) for 20 minutes on ice.
Following PBS washes, cells were seeded on slides (Superfrost;
Menzel-Glaser, Braunscheig, Germany) that were coated with
poly-L-lysine (0.01%; Sigma) and mounted in Mowiol
(Calbiochem, La Jolla, CA). Slides were analyzed on a Leica confocal
microscope and acquisitions were performed using an Agfa CoolSpan
camera and the MetaMorph software. For comparative analyses, all
photographs were taken using the same exposure conditions.
Expression of the HTLV receptor on human T lymphocytes is induced by TCR engagement A 215-amino acid truncation of the SU of HTLV Env, herein referred to as HRBD, retained the capacity to bind the HTLV Env receptor as monitored by its ability to specifically interfere with HTLV Env-mediated cell binding, cell fusion, and infection (F.J.K., E. N. Garrido, N.M., M.S., J.-L.B., manuscript in preparation).16 This truncated fragment fused at its C-terminus to a rabbit Fc-tag was used to study HTLV receptor expression on human T-cell subsets. Binding experiments were first validated in the Jurkat T-cell leukemia cell line. As previously demonstrated using the entire HTLV SU,15 HRBD bound efficiently to these cells (Figure 1A). PiT-2, the receptor for amphotropic MLV Env,20 is expressed on all T-cell subsets,21 and as such was used as a control throughout this study. As expected, binding of an Fc-tagged amphotropic MLV Env SU fragment (ARBD) was readily detectable in Jurkat cells (Figure 1A). Significant binding of the HRBD to Jurkat T cells was observed as early as 30 minutes after incubation at either 21°C or 37°C, but not at 4°C. In contrast, binding of the amphotropic RBD (ARBD) was observed at all 3 temperatures (data not shown). Whether these differences involve conformational changes of the receptors, the envelopes, or other membrane components remains to be determined.
The in vivo profile of the HTLV receptor is not known and,
specifically, its expression on T lymphocyte populations has not yet
been elucidated. Using the HRBD construct, we were unable to detect binding to freshly isolated naive (CD45RA) or memory (CD45RO)
CD4+ or CD8+ lymphocyte subsets, although in
some donors low-level expression could be detected on a maximum of 5%
of lymphocytes (Figure 1B and data not shown). The lack of binding was
specific to HRBD because ARBD binding was
readily detectable on all lymphocyte subsets (Figure 1B and data not
shown). Significant differences between Jurkat cells and primary T
lymphocytes include cell cycle progression and their general
"activation" state. Thus, unlike Jurkat cells, primary T cells are
almost entirely in the G0 phase of the cell cycle and do
not express activation markers. To induce cell cycle progression and an
"activated" profile, T lymphocytes were activated through their
cognate antigen receptor (TCR) using To directly visualize the distribution of the HTLV receptor on
CD4+ T lymphocytes, we used an HRBD fused
directly to EGFP, referred to herein as HRBD-EGFP. In
agreement with the FACS data, HRBD-EGFP binding was not
detected on unstimulated lymphocytes but was widely distributed on the
surface of activated lymphocytes (Figure
2A). The lack of HRBD-EGFP
binding was not due to an intrinsic difficulty in detecting staining in
small quiescent T cells because equivalent binding of an
TCR-induced HTLV receptor expression on CD4+ T lymphocytes precedes proliferation and requires de novo protein synthesis To determine the kinetics of HTLV receptor expression at the surface of activated CD4+ T lymphocytes, cells were stimulated with immobilizedCD3/CD28 mAbs and binding of
HRBD was assessed at 2, 4, 8, 24, 72, and 216 hours
following stimulation (Figure 3). Cell
surface expression of the HTLV receptor was compared with expression of
2 early activation markers, CD25 (IL-2R chain) and CD69 (Figure 3).
Cell surface CD69 and CD25 are detected at approximately 4 and 16 hours
after stimulation,17 respectively, whereas T lymphocytes
enter S phase at approximately 36 hours following TCR
engagement23 (J. Garcia-Sanz, personal oral communication,
April 2002). As expected, CD69 expression was detected on the
vast majority of cells within 8 hours after activation and reached
maximal levels at approximately 24 hours. The profile of CD25 induction
was slower; levels increased gradually between 4 and 24 hours and
plateau levels were maintained for 72 hours. The kinetics of HTLV
receptor expression was fairly comparable with that observed for CD25,
with a steady increase in receptor levels occurring between 4 and 72 hours after stimulation: the HTLV receptor was expressed on 30% to
40% of cells at 24 hours, whereas high receptor levels were detected
on the vast majority of cells at 72 hours (Figure 3).
HTLV receptor expression did not remain stable following TCR activation but diminished significantly as T lymphocytes returned to their resting state. In experiments performed with CD4+ T lymphocytes isolated from 4 individual donors, HTLV receptor expression decreased to basal levels between 8 and 14 days after stimulation. Expression of the CD69 and CD25 activation markers also decreased, albeit with different kinetics; CD69 levels were largely decreased by 72 hours, whereas CD25 levels returned to baseline with a longer lag time than the HTLV receptor (12-24 days). The TCR-induced proliferation of T lymphocytes is preceded by a 7-to
10-fold increase in protein synthesis.24 Indeed,
translation is crucial for the propagation of TCR-induced signals
because in its absence, activation is inhibited.25 To
assess whether surface expression of the HTLV receptor required de novo
protein synthesis, freshly isolated quiescent CD4+
lymphocytes were stimulated with
Induction of HTLV receptor expression in IL-7-stimulated neonatal T cells TCR engagement in primary T lymphocytes leads to the induction of an "activated" profile with high expression of CD25 and CD69 at the cell surface as well as an acquisition of a memory phenotype (Figure 3 and data not shown). Because the IL-7 cytokine serves as a T-cell survival factor without inducing an extensive activation profile,26-28 we assessed its effects on HTLV receptor expression. In T cells from APB, relatively low levels of CD25 were induced by IL-7 and cell surface expression of the HTLV receptor was marginal as monitored by binding of HRBD (Figure 5A). In contrast, surface expression of the HTLV receptor was detected in IL-7-treated neonatal CD4+ lymphocytes isolated from UC blood, albeit at significantly lower levels than those observed in TCR-activated lymphocytes (Figure 5A). UC-derived lymphocytes are particular in that they are naive T cells that have recently emigrated from the thymus and intriguingly IL-7 induces their proliferation29,30 but not the proliferation of APB CD4+ T cells (Figure 5B).
Expression of the HTLV receptor in IL-7-stimulated UC lymphocytes was not directly associated with expression of the CD25 activation marker as demonstrated by the findings that CD25 was induced to similar levels in IL-7-treated neonatal and adult CD4+ lymphocytes, whereas only the former bound HRBD at significant levels, and HTLV receptor expression in UC lymphocytes was not restricted to the CD25-expressing population (not shown). Expression of the HTLV receptor was not a constitutive characteristic of UC lymphocytes but was directly dependent on IL-7 treatment; HRBD binding was not observed in freshly isolated quiescent UC T lymphocytes. Moreover, on TCR engagement, HRBD binding to UC lymphocytes was induced to equivalent levels and with comparable kinetics as that observed in adult CD4+ lymphocytes (not shown). Thus, the HTLV receptor, which demonstrates a differential expression profile in IL-7-stimulated lymphocyte populations, represents a distinct activation marker in neonatal and adult CD4+ lymphocytes.
Previous to this study, vertebrate cell lines that do not express
the HTLV receptor had not been identified. Paradoxically, although T
cells appear to constitute a major HTLV reservoir in vivo, we report
here that quiescent T lymphocytes lack cell surface expression of the
HTLV receptor. However, we demonstrate that HTLV receptor expression is
induced under conditions where lymphocytes are stimulated to enter into
cell cycle, either via TCR engagement or in the case of neonatal T
cells, following IL-7 stimulation. Notably though, expression of the
HTLV receptor demonstrates a profile that is distinct from that of
other activation markers. The kinetics of HTLV receptor expression was
less rapid than that of the CD69 activation marker in TCR-stimulated
cells. Moreover, the induction and down-regulation of the IL-2R In the context of TCR engagement, expression of the HTLV receptor was not limited to any particular T-cell subset; rather, it was detected on naive and memory lymphocytes as well as on both CD4+ and CD8+ populations. Additionally, it should be noted that induction of HTLV receptor expression on naive T lymphocytes largely preceded the acquisition of a memory phenotype as acquisition of the memory CD45RO marker31 generally requires between 4 and 6 days under the conditions of TCR stimulation used here.32 The timing of HTLV receptor expression also preceded DNA synthesis, because the former was detected at 4 to 8 hours after TCR stimulation, whereas the latter generally begins at approximately 36 hours.23 Indeed, we found that HTLV receptor expression was independent of DNA synthesis. Treatment of TCR-stimulated T cells with an agent that blocks cell cycle progression at the end of the G1 phase (aphidicolin) did not abolish up-regulation of the HTLV receptor (S.K. and N.M., unpublished observations, September 2002). Expression of the HTLV receptor was strictly dependent on de novo protein synthesis. It has been shown that prior to T-lymphocyte proliferation, there is a 7- to 10-fold increase in protein synthesis and a 30- to 40-fold augmentation in mRNA synthesis.33 This "pre-proliferation" characteristic appears to be a particularity of T lymphocytes and is not observed in other cell types. The required pre-proliferation burst in mRNA/protein synthesis likely results from the extremely low metabolic rate of resting G0 T lymphocytes, which make up the vast majority of the circulating T-lymphocyte pool. Thus, it is intriguing to speculate that it is this low metabolic rate that accounts for the fact that T lymphocytes are the first and only cell type, identified to date, which do not constitutively express the HTLV receptor. Notably, Wodarz and Bangham have recently used a mathematical model to suggest that the rate of evolution of HTLV-1 is limited by the restricted availability of activated uninfected T cells, irrespective of the viral load.34 Distinctions between CD4+ and CD8+ T cells in serving as a reservoir for HTLV in vivo are probably not due to expression of the receptor itself, because we found that binding of HRBD depended on similar activation requirements and kinetics in these 2 cell types. Therefore, the distinct in vivo characteristics of these 2 cell types with regard to HTLV might be due to differences in the postentry steps of the infection. The precise associations between HTLV receptor expression, T-cell cycle progression, and infection remain to be elucidated, but our data suggest that quiescent and activated CD4+ and CD8+ T lymphocytes will provide important models in which to evaluate these questions. Because of the previous lack of adequate tools and the cytotoxicity of
the HTLV envelope, few of the molecular mechanisms regulating HTLV
binding at the cell surface have been elucidated. On the other hand, a
great deal of work has been performed with the HIV retroviral envelope
and it is generally accepted that binding of the SUgp120 HIV-1 envelope
glycoprotein to its receptors results in receptor
cocapping.35 Notably, HTLV Env was widely distributed on
target cells, as assessed by confocal microscopy (Figure 2), and no
capped structures were observed. Moreover, under conditions where
capping was induced with an antibody directed against the CD3 In conclusion, the absence of a functional HTLV receptor on quiescent CD4+ lymphocytes and its expression for a short period of time following TCR stimulation are likely to be crucial for the constitution of these cells as HTLV-1 reservoirs in vivo. In the case of neonatal T cells, our results suggest that a narrow window of susceptibility to HTLV-1 infection would result from either TCR stimulation or on contact with the IL-7 cytokine. Neonatal lymphocytes differ from their adult counterparts in that the former represent, almost solely, recent thymic emigrants. Thus, our finding that IL-7-stimulated neonatal T cells express the HTLV receptor suggests a possible mechanism via which HTLV can be transmitted from an infected mother to "nonactivated" recent thymic emigrants in the infant. The data presented here lay the groundwork for further in vitro and in vivo studies directed toward elucidating the pathophysiology of HTLV-1 infection and the role of the HTLV receptor in the T-cell activation process.
We are indebted to C. Boyer and the maternity staff at Clinique St Roch (Montpellier) without whose assistance this study would not have been possible. We thank P. Travo for expert advice on confocal microscopy, C. Mongellaz and L. Swainson for their support, and all the members of our laboratories for insightful discussions.
Submitted September 3, 2002; accepted October 7, 2002.
Prepublished online as Blood First Edition Paper, October 17, 2002; DOI 10.1182/blood-2002-09-2681.
N.M. and S.K. are funded by the Ecole Normale Supérieure (ENS) de Lyon and the European Community (HPMF-CT-2000-01035), respectively. F.J.K. has been funded by an award from the Philippe Foundation and successive fellowships from the Agence Nationale de Recherche sur le SIDA (ANRS), Association pour la Recherche sur le Cancer (ARC), and the Fondation de France. J.-L.B., N.T., and M.S. are supported by INSERM. This work was supported by grants from ARC and the Association Française contre les Myopathies (AFM) (M.S. and N.T), the ANRS and the March of Dimes (N.T.), and Fondation de France (M.S.).
N.M. and S.K. contributed equally to this work.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Naomi Taylor or Marc Sitbon, Institut de Génétique Moléculaire de Montpellier, 1919 Route de Mende, 34293 Montpellier, Cedex 5, France; e-mail: taylor{at}igm.cnrs-mop.fr or sitbon{at}igm.cnrs-mop.fr.
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  M. Lavanya, S. Kinet, A. Montel-Hagen, C. Mongellaz, J.-L. Battini, M. Sitbon, and N. Taylor Cell Surface Expression of the Bovine Leukemia Virus-Binding Receptor on B and T Lymphocytes Is Induced by Receptor Engagement J. Immunol., July 15, 2008; 181(2): 891 - 898. [Abstr |
Top
Abstract
Introduction
epitope of the TCR, neither capping nor a coaggregation of the HTLV
receptor was detected. Because TCR engagement results in the clustering
of rafts,