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Journal of Virology, March 2001, p. 3028-3033, Vol. 75, No. 6
Department of
Medicine1 and Department of
Immunology,4 University of Toronto,
Department of Microbiology, Mount Sinai
Hospital,5 and University Health
Network,2 Toronto, Ontario, Canada, and
Emory University Vaccine Center, Atlanta,
Georgia3
Received 15 September 2000/Accepted 14 December 2000
A vigorous expansion of antigen-specific CD8+ T cells
lacking apparent effector function was observed in a rhesus macaque
acutely infected with the simian immunodeficiency virus (SIV) strain
SIVmac239. Antigen-specific CD8+ T cells were identified
using antigenic-peptide class I major histocompatibility complex
tetramers. As many as 8.3% of CD8+ cells recognized the
Mamu-A*01-associated SIV epitope Gag181-189 (CTPYDINQM); however, these cells
demonstrated no effector function when presented with peptide-incubated
targets, as measured by intracellular cytokine staining for gamma
interferon (IFN- CD8+ T cells are thought
to play an important role in the control of human immunodeficiency
virus type 1 (HIV-1) (21, 24, 26) and simian
immunodeficiency virus (SIV) (12, 28) infection. Induction
of HIV-specific CD8+ T-lymphocyte responses is associated
with the control of plasma viremia (23) and correlates
with delayed disease progression in adults (3) and infants
(26). The quantitation of antigen-specific CD8+ T cells in vivo has been greatly facilitated by the
use of tetrameric complexes of antigenic peptide and MHC, which has
brought about significant advances in the understanding of the dynamics
of T-cell responses (2, 25). Current reviews of tetramer
technology concur that there is a strong quantitative correlation
between tetramer binding activity and functional measures of
antigen-specific CD8+ T-cell activity (6, 19).
However, several authors have recently reported examples of circulating
antigen-specific CD8+ T cells that appear to be
functionally inactive. For example, Zajac et al. have reported that in
lymphocytic choriomeningitis virus-infected CD4-deficient mice,
antigen-specific CD8+ T cells do not have the ability to
secrete gamma interferon (IFN- Here, we report a vigorous expansion of SIV-specific CD8+ T
cells without effector function during an acute SIVmac239 infection. The nonresponsive cells did not produce cytokines or have cytolytic activity against a panel of SIV peptide antigens, despite having tetramer reactivity. However, incubation of the non-responsive cells
with IL-2 in the absence of antigen restored the responses and the
quantitative correlation between tetramer binding and cytokine
secretion. The apparent nonresponsiveness of the antigen-specific CD8+ cells may reflect one mechanism by which
immunodeficiency viruses escape the immune response.
Tetramer binding and IFN-
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.6.3028-3033.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Simian Immunodeficiency Virus (SIV) Infection of a Rhesus Macaque
Induces SIV-Specific CD8+ T Cells with a Defect in Effector
Function That Is Reversible on Extended Interleukin-2
Incubation
ABSTRACT
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Abstract
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References
), interleukin-2 (IL-2) production, or direct
cellular lysis. Similar results were observed with three other SIV
peptide antigens. Nonresponsiveness did not correlate with apoptosis of
the CD8+ cells, nor were cells from this macaque impaired
in their ability to present peptide antigens. Associated with the
nonresponsive state was a lack of IL-2 production and decreased
IL-2 receptor expression. Exogenous IL-2 treatment for 1 week in the
absence of antigenic stimulation restored antigen-specific responses
and the quantitative correlation between tetramer recognition and antigen-responsive IFN- secretion. This case report suggests a
regulatory mechanism that may impede the effector function of antigen-specific T cells during acute infection with SIV or human immunodeficiency virus in some cases. This mechanism may participate in
the failure of the immune system to limit infection.
TEXT
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Abstract
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References
) in response to antigen, unlike the
analogous population in CD4-normal mice (34). Spiegel et
al. have reported the persistence of high frequencies of HIV
peptide-specific CD8+ cells, unable to secrete IFN- in
response to antigenic peptide, in an HIV-1-infected individual with
very low CD4+ T-cell counts (29). Lee et al.
have shown the existence in a melanoma patient of melanoma-specific
CD8+ cells that fail to exhibit cytolytic activity in vitro
or to produce interleukin-2 (IL-2), IL-10, IFN- or tumor necrosis
factor alpha in response to antigen (15). Finally, Lechner
et al. recently showed that in acute hepatitis C virus infection,
tetramer-positive cells are defective in IFN- production during the
acute phase but recover over time. They and others have described these
cells as "stunned lymphocytes" (14).
staining.
Comparison of the
frequencies of tetramer-positive cells and cells responding in an
intracellular cytokine assay revealed nonresponsive SIV-specific
CD8+ cells in an acutely infected but not a chronically
infected macaque. We compared the frequency of antigen-specific
CD8+ T cells (as measured by major histocompatibility
complex [MHC]-antigenic peptide tetramers) to the frequency of
antigen-reactive cells (as measured by an intracellular cytokine assay)
in two infected Mamu-A*01-positive macaques (Mamu-A*01 typed by
PCR with sequence-specific primers by the method of Knapp et al.
[13]). One macaque, designated RPb4, was acutely
infected with an intravenous challenge of highly pathogenic SIVmac239
(5). The other, designated RLc5, was chronically infected
with SHIV-89.6, a nonpathogenic chimera of SIV and HIV (27). The two viruses have a common Gag antigen. For RPb4,
peripheral blood mononuclear cells (PBMC), lymph node cells, and spleen
cells were cryopreserved 30 to 60 days after infection
(18). For RPb5, only cryopreserved PBMC were available.
Thawed cells were stained with the Mamu-A*01 tetramer complex with the
dominant SIV Gag epitope Gag181-189 (CTPYDINQM).
In the acutely infected macaque, RPb4, high levels of
Gag181-189-tetramer-specific CD8+ T cells were
detected in each cellular compartment, with the highest frequency being
found in lymph nodes and spleen (PBMC, 2.3% ± 0.5% [Fig.
1A]; lymph node cells, 8.3% ± 0.4%; spleen cells, 7.9% ± 0.8% [average of three
determinations]). In the chronically infected macaque, RLc5, for which
only PBMC were available, tetramer-positive cells were also detected
(PBMC, 0.63% [two determinations] [Fig. 1A]).
View larger version (59K):
[in a new window]
FIG. 1.
(A and B) Tetramer binding does not correlate with
IFN- secretion in the acutely infected macaque RPb4. (A) PBMC from
macaque RPb4 acutely infected with SIVmac239 and macaque RLc5
chronically infected with SHIV89.6 were stained with the
Mamu-A*01-Gag181-189 tetramer. Values in the upper right
quadrants represent the percentage of CD3+ CD8+
cells reactive with the tetramer. A total of 100,000 events were
analyzed. (B) IFN- secretion by unstimulated, phorbol myristic acid
(PMA)-ionomycin (mitogen)-treated, or Gag181-189-incubated
cells. (C and D) IL-2 treatment for 1 week recovers antigen
responsiveness and the correlation with tetramer binding. (C) IL-2
treatment for 1 week in the absence of antigen restored IFN-
secretion of RPb4 splenocytes in response to a panel of SIV epitopes.
(D) T-cell binding to the corresponding tetramer in each case. The
rightmost panel in panel D shows staining with an irrelevant tetramer,
HLA-A2 with the antigenic Epstein-Barr virus peptide GLCLVAML.
Values indicate the percentage of CD3+
CD8+ cells in the labeled quadrant. Data are representative
of three experiments.
in response to
Gag181-189 (Fig. 1B), concordant with the number of cells
staining with the Gag181-189 tetramer (0.63%). However,
PBMC (Fig. 1B) and cells from the LN or spleen (data not shown) of RPb4
did not produce IFN- or IL-2 in response to Gag181-189,
despite the high frequency of tetramer-staining CD8+
cells (0.06% IFN- responsive, equivalent to background,
compared to a tetramer-binding population of 2.4%).
The nonresponsiveness of antigen-specific T cells in the
acutely infected macaque was also observed for three other
epitopes for which tetramers were available. To determine
whether the defect in peptide recognition in RPb4 was
restricted to the Gag181-189 epitope, we measured the
IFN- response to other known Mamu-A*01-restricted epitopes including Env234-242 (CAPPGYALL),
Env626-634 (TVPWPNETL), (7),
and Tat28-35 (STPESANL [D. Watkins, Wisconsin Regional Primate Center, personal communication]). In the
acutely infected macaque, RPb4, no response to any of the epitopes could be measured, despite tetramer-staining cell
frequencies ranging from 2.9 to 4.7% of CD8+ T cells (data
not shown). A mitogen response was intact in both animals, since
CD8+ T cells responded with IFN- production to
stimulation with phorbol myristic acid and ionomycin (Fig. 1B).
These results suggest that acute SIV infection with the pathogenic
viral strain SIVmac239 induced a nonresponsive state in
antigen-specific CD8+ T cells to subsequent SIV antigen
stimulation. The possibility that the nonresponsive state of
CD8+ T cells might extend to non-SIV antigens could not be
examined because of the lack of defined peptide recall antigens in the macaque model system.
IL-2 recovery of the IFN- response.
Culture of the spleen
cells of RPb4 with IL-2 (without antigen) for 1 week restored the
responsiveness to peptide. It has been demonstrated that T-cell
proliferation is triggered by the interaction of IL-2 and its receptor
following T-cell activation (30). A lack of IL-2 during
T-cell activation can result in anergy of the responding cells
(17). In our studies, the CD8+ T-cell
unresponsiveness in RPb4 was accompanied by undetectable levels of IL-2
production in response to Gag181-189 (data not shown).
This, together with a deficit of CD4+ cells in the
nonresponsive animal (only 11% of total CD3+ cells [see
below]), led us to postulate that low levels of IL-2 might be related
to CD8+ cell nonresponsiveness. Spleen cells of RPb4 were
cultured with recombinant human IL-2 (20 U/ml) for 7 days without
antigenic stimulation. This culture restored the ability of
CD8+ T cells to produce IFN- in response to
subsequent antigenic stimulation by all peptides tested, although with
a somewhat reduced mean IFN- expression (Fig. 1C). After recovery,
the frequencies of IFN--producing CD8+ T cells
from the spleen were 2.4% against Gag181-189, 1.6% against Env234-242, 0.8% against
Env626-634, and 1.0% against Tat28-35. The
frequencies of tetramer-staining cells for the same antigens were in
good concordance, ranging from 43 to 76% of responding cells (Fig.
1D). Incubation of RPb4 spleen cells with IL-2 for 6 h in the
presence of Gag181-189 peptide did not restore the
response, indicating the requirement for the longer incubation.
Addition of a monoclonal antibody to IL-2 during the IL-2 culture
blocked the recovery of the IFN- response (data not shown). Thus,
IL-2 treatment restored both the antigen-specific response and the
correlation between responding cell frequency (IFN- assay) and
antigen recognition frequency (tetramer assay).
Lytic activity.
Deficits in the lytic activity of RPb4 cells
could be restored by a 1-week incubation in IL-2 in the absence of
antigen. The primary cytotoxic activity of splenocytes and PBMC from
macaque RPb4 and PBMC from RLc5 was tested by using freshly thawed
cells as effectors in a standard 5-h chromium release assay
(20). Mamu-A*01-transfected 721.221 cells (a cloned
Epstein-Barr virus-transformed human B-cell line with homozygous
deletions of the MHC class I loci [1]) were used as
targets in the assay. No primary cytotoxic T-lymphocyte activity
against Gag181-189, Tat28-35, Env234-242, or Env626-634 was found in either
splenocytes (Fig. 2A panel i) or PBMC
(Fig. 2A panel iii, Gag181-189 only) from the acutely
infected macaque, RPb4. A very low level of
Gag181-189-directed cytotoxicity was detected in the chronically infected macaque RLc5 (Fig. 2A panel iii), correlating with
the lower frequency of Gag181-189-specific
CD8+ T cells in this animal. After 1 week of incubation
with IL-2 in the absence of antigen, splenocytes from RPb4 (Fig. 2A
panel ii) lysed all peptide-incubated targets tested, with the
exception of the irrelevant control (Gag2-10,
GVRNSVLSG; lysis less than 6% [data not shown]). PBMC
from both animals lysed Gag181-189-incubated targets after
a conventional in vitro boost with peptide plus IL-2 for 10 days (20 U
of IL-2 per ml plus 5 µg of peptide per ml) (Fig. 2A panel iv).
|
Phenotypic analysis of T cells. PBMC from RPb4 and the chronically infected macaque RLc5 were examined by flow cytometry for the expression of a number of phenotypic markers. A difference in the CD4+/CD8+ T-cell ratio (11:89 in RPb4 versus 50:50 in RLc5) was found, while CD3+ T cells remained in similar proportion to total PBMC (67.8% in RPb4 versus 68.3% in RLc5). This association of a relative CD4+ T-cell deficit in RPb4 with CD8+ T-cell nonresponsiveness is consistent with the observation of Zajac et al. of CD8+ T-cell nonresponsiveness to LCMV antigens in mice lacking CD4+ T cells (34). Further phenotypic analysis showed that Gag181-189 tetramer-binding CD8+ T cells in the unresponsive macaque were positive for CD28+ (54% on CD8+ from RPb4 versus 87% on CD8+ from RLc5) but negative for CD45RA (12% on CD8+ from RPb4 versus 13% on CD8+ from RLc5). Although memory T-cell phenotypes have not been fully defined in macaques, the results suggest that the nonresponsive T cells are memory cells but not effectors, applying the subset definitions used in humans (11). The activation marker Mamu-DR (the homologue of HLA-DR) was expressed at low levels on tetramer-positive CD8+ T cells in both macaques (5% on RPb4 and 7.6% on RLc5).
IL-2R
on unresponsive CD8+ T cells.
The
high-affinity IL-2 receptor alpha (IL-2R) chain (CD25) is known to
be important in regulating the T-cell response to antigen
(22). Decreased expression of IL-2R has been found on
CD8+ T cells from HIV-infected individuals
(32). Therefore we examined the expression of CD25
on Gag181-189 tetramer-positive CD8+ T cells.
We found that CD25 was expressed at low levels on these T cells in both
macaques (1.6 and 7.3% of tetramer-staining CD8+ T cells
for acutely infected RPb4 and chronically infected RLc5, respectively)
before in vitro antigenic stimulation (Fig. 2B). After 6 h of
stimulation with Gag181-189 peptide, 80% of the
Gag181-189 tetramer-positive CD8+ T cells from
RLc5 expressed CD25 whereas only background levels of staining (6.4%)
were observed in RPb4. However, after a 7-day culture of cells with 20 U of IL-2 per ml, 31 and 35% of antigen-specific CD8+ T
cells expressed CD25 in RPb4 and in RLc5, respectively. Subsequent stimulation with Gag181-189 peptide increased the
expression of CD25 on antigen-specific CD8+ T cells to 88%
in RPb4 and 72% in RLc5. Thus, the combination of IL-2 preculture and
antigen exposure boosted the frequency of CD25-positive
tetramer-reactive cells in the nonresponsive macaque to a similar level
to that seen in the chronically infected macaque. A related finding was
reported by Groux et al. (10), who found that that
CD4+ T cells rendered anergic by culture with IL-10 failed
to upregulate CD25 in response to antigen but that preculture with IL-2
restored CD25 expression in response to antigenic stimulation. On the
other hand, failure to express CD25 in the presence of exogenous IL-2 correlated with a failure to reverse the anergic state. This parallel between the induction of CD25 and the recovery of the T-cell response suggests that defective CD25 expression may be involved in T-cell nonresponsiveness.
Antigen presentation.
Cells from the unresponsive macaque
functioned normally to present antigen. HIV-1 has evolved a mechanism
of immune evasion involving the downregulation of MHC class I
expression mediated by the viral protein Nef (4, 9). Such
a downregulation could affect the ability of cells to present
exogenously added peptide antigens. To address the ability of
unstimulated splenocytes from the acutely infected macaque RPb4 to
present antigen, spleen cells were pulsed with Gag181-189
peptide for 2 h and then washed extensively. They were incubated
as antigen-presenting cells (APC) with autologous spleen cells
previously cultured for 7 days with IL-2. The frequency of
IFN--producing CD8+ T cells was similar to that seen on
direct addition of Gag181-189 peptide (10 µg/ml) to the
IL-2-cultured cells (4.6 and 3.3%, respectively [Fig. 2C]). Thus,
APCs from the unresponsive macaque can present antigen, indicating that
the CD8+ T-cell unresponsiveness seen in untreated cultures
was not due to defective antigen presentation.
Apoptosis. T cells from HIV-infected persons are highly prone to in vitro spontaneous and activation-induced apoptosis (8), and this tendency has been implicated in T-cell hyporesponsiveness in HIV disease (16). We therefore examined the role of apoptosis in the antigen responses of RLc5 and RPb4. Annexin V was used as a marker of apoptosis, and propidium iodide was used to differentiate apoptotic from necrotic cells (31). No significant necrosis (propidium iodide-positive annexin V-positive phenotype) was seen in any assay (data not shown). Cells from each macaque (freshly thawed and not pretreated with IL-2) were stained immediately for annexin V or were stimulated with Gag181-189 peptide for 6 h, followed by staining and flow cytometric analysis. Untreated, total CD8+ cells in both macaques had a background frequency of apoptosis of about 10% (data not shown). Gag181-189 tetramer-positive CD8+ cells in untreated samples were positive for the apoptotic marker at a higher frequency (35% for RPb4 and 28% for RLc5 [data not shown]), indicating that there was more apoptosis in the antigen-specific cell population than in the total CD8+ T-cell population in both animals. Incubation with Gag181-189 peptide for 6 h increased the frequency of apoptotic tetramer-positive cells in both animals (58% for RPb4 [ratio of 3.6 tetramer-positive annexin V-positive cells to 3.2 tetramer-positive annexin V-negative cells] and 47% for RLc5 [0.14:0.18] [Fig. 2D]). However, it is clear that the slightly higher frequency of apoptotic tetramer-positive cells in RPb4 was not sufficient to fully account for the nonresponsive T-cell phenotype in that animal compared to RLc5. In other experiments where cells were thawed and treated with IL-2 alone for 1 week, we observed that the total lymphocyte counts changed by only ±15% between the initiation and termination of the cultures (data not shown). The frequency of Gag181-189 tetramer-positive spleen CD8+ T cells, however, declined from 7.1% (data not shown) to 4.1% (Fig. 1D) over the same period, which suggests that apoptotic tetramer cells observed in the untreated sample were lost, as expected, during the week-long incubation.
In summary, acute SIVmac239 infection of a rhesus macaque resulted in high frequencies of SIV-specific CD8+ T cells without apparent effector function. Antigen responsiveness in the acutely infected macaque, as measured by IFN- production and cytotoxic
T-lymphocyte activity was restored after a 1-week incubation with IL-2,
as was the correlation between tetramer binding and IFN- production.
A plausible interpretation of the data is that CD8+ T-cell
unresponsiveness resulted from a lack of CD4+ T-cell help
and IL-2 production, with a resulting defect in CD25 induction. The
lack of CD8+ T-cell response that we observed in this
acutely infected macaque may be a result of a specific mechanism used
by SIV to escape immune surveillance or may reflect a generalized
depletion of cofactors like IL-2 and CD4+ T-cell help
necessary for the proper activation of mature, antigen-exposed CD8+ T-cell effectors. In either case, it will be important
to understand the frequency and implications of the phenomenon in
retroviral and potentially other viral infections to elucidate how to
induce and and sustain beneficial virus-specific CD8+
T-cell effectors.
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ACKNOWLEDGMENTS |
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We thank Francois Villinger for Emory University cryopreservation of cells and Shari Lydy (Emory University) for Mamu-A*01 phenotyping of macaques. SHIV89.6 was graciously provided by K. A. Reiman, and SIVmac239 was provided by R. C. Desrosiers. D. I. Watkins kindly provided Mamu-A*01-transfected 721.221 cells. We also thank Bing Li (University of Toronto) for technical assistance.
This work was funded under NIH grant P01 AI43045. Further funding was provided by the Toronto Hospital Foundation Skate the Dream Fund. K.S.M. is a Career Scientist of the Ontario HIV Treatment Network.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Microbiology, Mount Sinai Hospital, 600 University Ave., Toronto, ON M5G 1X5, Canada Phone: (416) 586-8879. Fax: (416) 586-8746. E-mail: KMacDonald{at}MtSinai.on.ca
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Journal of Virology, March 2001, p. 3028-3033, Vol. 75, No. 6
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.6.3028-3033.2001
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