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1-Producing Immunoregulatory CD8+ T Cells1
Departments of
*
Microbiology and Immunology,
Medicine, and
Pharmacy, University of North Carolina, Chapel Hill NC 27599
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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25% of
HIV+ donors produced TGF-
1 in response to
stimulation with HIV proteins or peptides. The production of
TGF-1 was sufficient to significantly reduce the IFN-
response of CD8+ cells to both HIV and vaccinia virus
proteins. Ab to TGF- reversed the suppression. We found the source
of the TGF-1 to be predominantly CD8+
cells. Different peptide pools stimulated TGF-1 and
IFN- in the same individual. The TGF-1 secreting
cells have distinct peptide specificity from the IFN- producing
cells. This represents an important mechanism by which an HIV-specific
response can nonspecifically suppress both HIV-specific and unrelated
immune responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To measure the variability of HIV-specific CTL activity among
HIV-infected individuals, we enumerated CD8+
responses using the expression of IFN- (15, 16). Flow
cytometric methods of measuring intracellular cytokines provide us with
information on the phenotype as well as the proportion of the cells
producing a particular cytokine (13, 17, 18, 19). Recent and
past studies have shown that most CTL produce IFN- in both mice and
humans (13, 20, 21). HIV-specific epitopes have also been
mapped by measuring IFN- release (22). In our lab, we
found a strong correlation
(r2 = 0.9968) of
HIV-specific CTL lysis with IFN- responses as detected by flow
cytometry (M. L. Garba and J. A. Frelinger, unpublished
observations).
HIV infection leads to a variety of disturbances in cytokine expression
(23, 24). TGF- is an anti-inflammatory cytokine.
TGF- is a multigene family composed of five described members. The
unique inhibitory effects of TGF- are mostly mediated by the
TGF-1 (25). TGF- has been
reported to be up-regulated by tat in HIV-infected cells
(26, 27). This enhanced TGF- expression has been
postulated to lead to suppression of both B and T lymphocyte function
including inhibition of other cytokines such as IFN-
and -
(28, 29). In this paper, we present evidence that HIV Ags
can induce in vitro TGF-1 secretion by
CD8+ T cells that is able to inhibit IFN-
responses to HIV and unrelated Ag.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Forty unselected HIV+ patients and 20
low-risk donors were recruited at the University of North Carolina
(Chapel Hill, NC) using a protocol approved by the University of North
Carolina Institutional Review Board. Blood samples were
collected from the donors after obtaining their informed consent. The
only criteria for inclusion was HIV infection. Patient
characteristics are summarized in Table I
. All but one of the patients were expected to have been
previously exposed to vaccinia due to small pox vaccination (because of
their ages).
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PBMCs were isolated from donor blood using Ficoll-Paque. An aliquot was then transformed using EBV and the remainder was stored in liquid nitrogen for future use.
Viruses
Either control vaccinia-SC11 (obtained from J. Bennink, National Institute of Allergy and Infectious Diseases) or vaccinia-GPE3 (VV-ABT 408-6-1, containing clade B HIV-1 IIIB gag, pol, and env; Therion Biologics, Cambridge, MA) was used. The two viruses were propagated as previously described (30).
Peptides
HIV peptide sets (20 mer overlapping by 10) representing the
entire length of the env, gag, and pol regions (HIV-1 MN env, HIV-1
HXB2 gag, and HIV-1 HXB2 pol) were obtained from the AIDS Research and
Reference Reagent Program of the National Institutes of Health,
which can be accessed online
(http://www.aidsreagent.org/ecommerce/default.cfm?action =
catList&CatID = 46628). Pools of 50 peptides (2 env, 1 gag, and 2
pol pools, respectively; final total peptide concentration of 1 mg/ml)
were made. Preliminary experiments showed that this was sufficient to
induce IFN- responses in accord with the reports of others
(31, 32, 33, 34). Patient samples were stimulated with each pool
separately.
Vaccinia stimulation of PBMC
PBMC were stimulated by coculture with autologous transformed B cell lines (10:1 ratio) infected with the appropriate vaccinia virus (multiplicity of infection = 5) as previously described (35, 36). During the last 3 h of culture, 10 µg/ml (final concentration) of brefeldin-A was added to the wells. As additional controls, PBMCs suspended in medium containing IL-2 and IL-7, but not cultured with B cells infected with vaccinia or any other virus, were used as unstimulated controls for the vaccinia-stimulated cultures. The optimum time of stimulation was determined in previous experiments and the same conditions were maintained for all vaccinia or vaccinia-GPE experiments. For all experiments, the unstimulated background was subtracted.
Peptide stimulation of PBMC
PBMC were thawed and resuspended in complete culture medium at a concentration of 4 million PBMC/ml and stimulated with peptide pools (final concentration 100 ng/ml of each peptide) along with CD28 and CD49d (BD Biosciences, San Diego, CA). The cells were then incubated for 18–24 h and brefeldin-A (final concentration of 10 µg/ml) was added during the last 4 h of stimulation. The optimum length of stimulation was determined by previous experiments (37).
Intracellular cytokine staining for IFN- and
TGF-1
One step surface and intracellular staining was performed as
previously described (31, 38).
TGF-1 staining has been previously described
by our laboratory (39).
Conjugated Abs used were specific for CD3 (clone:
HIT3a), CD4 (clone:
RPA-T4), CD8 (clone:
RPA-T8), CD69 (clone: FN50), and anti-IFN-
(clone: B27) (BD PharMingen, San Diego, CA). We also used
anti-TGF-1 (clone: TB21 (40))
(a gift from IQ Products, Groningen, The Netherlands). The cells
were stained with anti-CD3, anti-CD8, anti-CD69, or
anti-CD4 and anti-IFN-. TGF--producing cell lines (number
CR 2159, LS411N; American Type Culture Collection, Manassas, VA)
were used as positive controls and nonstimulated PBMC was used as a
negative control. The cells were then analyzed by flow cytometry
(FACScan; BD Biosciences). To analyze the data, a minimum of 20,000
list mode events were collected using FACScan Cyclops software and then
the WINLIST V4.0 software (Verity, Topsham, ME) was used for
analyses. CD3+ cells were first gated, followed
by CD4+ or CD8+ cells.
IFN- and TGF-1 production by
CD4+ and CD8+ cells is
reported as the percentage of total CD4+ or
CD8+ cells respectively.
ELISA
Human TGF-1 and IFN- ELISA kits
(Quantikine; R&D Systems, Minneapolis, MN) were used to measure
TGF-1 and IFN- in culture supernatants
according to the manufacturer’s recommendation. The
TGF-1 assay measures total
TGF-1.
TGF-1 neutralization experiments
Cells from six donors were stimulated using vaccinia-SC11
or vaccinia-GPE as described in the previous sections. Three different
wells of vaccinia-GPE, and one well of vaccinia-SC11 stimulations, were
set up in a 24-well culture plate. The first well of the vaccinia-GPE
stimulation was left untreated and either 0.5 µg/ml anti-human
TGF-1 or an isotype matched Ab control (R&D
Systems) was added in the other two. This was followed with surface and
intracellular staining 24 h later as described above.
Statistical analysis
For all flow cytometry experiments responder frequencies were determined using WINLIST V4.0 software (Verity). Data were collated and statistics generated using SPSS 8.0 for Windows (SPSS, Chicago, IL). Data from the ELISA experiment was expressed in picograms per milliliter and plotted either as means (column graphs) or correlation curves. t tests were used to compare means and obtain p values while r2 was determined for correlation graphs.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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responses
The IFN- response of 20 low-risk individuals to vaccinia
virus or recombinant vaccinia virus expressing HIV proteins gag, pol,
and env (vaccinia-GPE) was tested. PBMCs were isolated and
stimulated with transformed B cells infected with each of the two
viruses. The percentage of IFN- cells responding to the vaccinia
control was subtracted from the percentage of IFN- cells
responding to vaccinia-GPE recombinant virus to determine the
HIV-specific response. As expected for HIV low-risk individuals, the
mean was close to zero (0.04%) with a range of -0.76–1% and SD of
0.59%. This established the normal range of the assay in controls.
HIV-infected donors were defined as either responders or
suppressors: if responses were greater or less than ± 2 SD of the
control group mean and those within this range were classified as
indeterminate (Fig. 1A).
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Forty HIV+ donors were analyzed in the same
way as the low-risk donors. We had expected that we would see that the
HIV+ donor response would all be equal or greater
than the control vaccinia responses. Fifteen of 40 donors had
vaccinia-GPE responses greater than controls, while 15 of 40 had
IFN- responses indistinguishable from controls. Surprisingly, 10 of
40 donors had vaccinia-GPE responses significantly less than the
controls (Fig. 1
A). Data for GPE-specific responses
from the 40 HIV+ individuals were classified,
based on the criteria defined above, as responders (vaccinia-GPE
> vaccinia), suppressors (vaccinia-GPE < vaccinia), or
indeterminate (vaccinia-GPE = vaccinia). The average vaccinia
responses for each of the three groups of HIV+
individuals were indistinguishable from those of the
HIV- individuals (Fig. 1B), demonstrating that they could all produce
IFN- responses. To test the precision of the assay, this analysis
was repeated with 20 of the donors using duplicate samples, but
performed several months apart. The results were identical in
classification and nearly identical in quantification
(r2 = 0.9082). We show an example of the
primary data which forms the basis of this classification. Fig. 1, C and D, shows the responses of a responder to
vaccinia Sc11 (C) and HIV-vaccinia (D). As can
largely be seen, there is a substantially higher number of
IFN-+ CD8+ cells in
D (4.19%) than C (1.89%). In contrast, a
suppressor donor shows a marked decrease (compare E (6.7%)
vs F (1.07%)).
HIV protein expression does not alter Ag presentation of vaccinia proteins
We were concerned that the expression of HIV proteins in the
recombinant vaccinia might alter the presentation of vaccinia proteins
and thus result in the apparent suppression of the vaccinia-specific
response. To test this, we compared the responses of the low-risk
donors to vaccinia and vaccinia-GPE. The IFN- responses to
vaccinia-GPE correlated closely with responses to control vaccinia
(r2 = 0.8899) in low-risk donors (Fig. 2A). Thus, the diminished
capacity to respond to HIV-vaccinia in HIV+
donors cannot be attributed to interference with Ag presentation. In
this group, only one donor was young enough to have not been
vaccinated. We suspect that the response of this individual (1%) is
linked to an EBV-specific response from the immortalized B cell lines
used as APCs in the experiment.
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and intracellular cytokine (ICC) assay
are highly correlated
To be certain that the ICC IFN- assays reflected secretion of
the cytokine, the ELISA and ICC measurements were compared in seven
HIV+ donors. There was excellent correlation
between the ELISA and the ICC assay (Fig. 2B;
r2 = 0.91) indicating that the total
secretion of the IFN- and the number of CD8+
cells producing IFN- as measured by these two methods are
equivalent. Thus the assays are both good measures of the IFN-
response.
Suppressors produce high levels of TGF-
We reasoned that suppression of unrelated vaccinia responses was
due to a regulatory response to HIV itself. We investigated production
of the potent immunoregulatory cytokine TGF-1.
We measured TGF-1 secretion in the cultures of
all responders and suppressors stimulated at least once with
vaccinia-GPE or control vaccinia. We have shown a
representative experiment that was repeated twice in three responders
and three suppressors, chosen based on the availability of sufficiently
large samples. Each experiment was set up in triplicate and the mean
values in picograms per milliliter were calculated. Responder cultures
(which showed good IFN- responses) produced very little
TGF-1 as measured by ELISA (Fig. 3A).
TGF-1 secretion in the suppressors was
significantly increased in the vaccinia-GPE stimulated cultures over
the control vaccinia-stimulated cultures. Because
TGF-1 is known to be anti-inflammatory, it
was likely that the reason for the lowered IFN- response
in the vaccinia-GPE-stimulated cultures was production of
TGF-1. Indeed, when IFN- and
TGF-1 from seven other patients were plotted,
there was a negative correlation between TGF- secretion and IFN-
secretion (r2 = 0.868; Fig. 3B).
Cultures with high TGF-1 produced little
IFN- and vice versa.
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1
To confirm that TGF-1 was the functional
immunoregulatory cytokine in vaccinia-GPE-stimulated cultures, we
reasoned that Ab to TGF-1 added to the
cultures would be able to reverse the suppressive effect.
TGF-1 neutralization experiments were
performed on stimulated PBMCs. Three independent experiments performed
in triplicate are summarized in Fig. 4.
Suppressor donor cells stimulated with vaccinia-GPE alone had lower CD8
responses than control vaccinia as before (p <
0.003). This effect was reversed with the use of
anti-TGF-1 Ab (p
< 0.002), but not by an isotype Ab control (p
> 0.7) confirming that TGF-1 was a critical
mediator of this suppressive effect. Indeed, after the addition of
anti-TGF-1, the cultures with vaccinia-GPE
and anti-TGF-1 produced higher IFN-
responses than cultures with vaccinia alone and significantly higher
than vaccinia-GPE cultures (p < 0.00001) and
vaccinia-GPE with isotype Ab cultures (p <
0.00001). This suggests that an IFN- response to HIV was suppressed
by TGF-1 as well and could now be revealed by
inhibiting the action of TGF-1. In contrast,
the responder cultures showed significant increase in IFN- in
vaccinia-GPE cultures with or without isotype Ab
(p < 0.00001) and in the presence of
anti-TGF-1 Ab (p
< 0.0001). However, there is no significant difference between
vaccinia-GPE cultures alone and vaccinia-GPE cultures with
anti-TGF-1 Ab (p
> 0.7).
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1 is predominantly
CD8+ cells
To determine which cells produced TGF-1,
we examined the cells from three patients stimulated with vaccinia or
vaccinia-GPE-infected autologous B cells (or peptide pools; data not
shown) and we determined the frequency of
TGF-1-producing T cells by intracellular
staining for TGF-1. The assays showed that
while both CD4+ and CD8+
cells produce TGF-1, 80% of the
TGF-1-producing cells are
CD8+ cells (Fig. 5, A and B). We were able to block the
TGF-1 staining of all the cells using human
rTGF-1, indicating that the response we were
measuring was TGF-1 production by
the cells (Fig. 5C). In Fig. 5D, we show a
histogram of simultaneous staining for both TGF-1 and
IFN- performed on the same cells. The figure shows that different
CD8+ cells are producing the two cytokines in
this patient and also confirms that suppressor patients have a smaller
proportion of IFN- producing cells. Two other patients give similar
results.
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1 production is peptide-specific
PBMC from eight suppressors and three responders were stimulated
with peptide pools to determine the HIV specificity of
TGF-1 production. We wished to know if the
peptides would stimulate TGF-1 production as
seen with the vaccinia-GPE virus and if the peptides stimulated the
production of both IFN- and TGF-1. Fig. 6 shows that responders produce IFN-
but not TGF-1, while suppressors produce
predominantly TGF-1 but little IFN-.
TGF-1 production was stimulated by at least
one peptide pool in all suppressors. None of the peptide pools
stimulated TGF-1 in the responders while we
had at least one peptide pool that produced IFN-. In
four of the eight suppressors, IFN- responses were stimulated by at
least one peptide pool. These data suggest that
TGF-1 and IFN- production are Ag-specific.
More importantly, it demonstrates that clones with distinct specificity
must respond by TGF- or IFN- production. Because the
patterns of stimulation by the peptide pools are not identical
among the patients, it show that the peptides themselves do not
stimulate TGF-1 production independent of TCR
engagement.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1, rather than the absence of cells
capable of responding to HIV Ags as has been previously proposed
(26, 27, 43). We also saw nonspecific suppression of the
vaccinia response. In other words, there was a suppression of both the
vaccinia and HIV-specific responses in the presence of an HIV-specific
stimulation as indicated by the lower percentage of IFN--producing
cells in the vaccinia-GPE culture compared with the vaccinia alone
culture (Fig. 1, E and F, and Fig. 4).
In individuals with a suppressor phenotype, the lack of both
HIV-specific IFN- response and the suppression of vaccinia-induced
IFN- responses were mediated by the active production of
TGF-1 (Figs. 3, A and
B). This is unrelated to the tat protein effects previously
reported (26) because tat is not expressed by vaccinia-GPE
and is not present in peptide pools. Furthermore, this suppression
cannot be due to TGF-1 production in the
culture by HIV-infected cells, because the same number of HIV-infected
PBMC are present in all cultures but only some peptide pools stimulated
TGF-1 production. The addition of Ab to
TGF-1 to the culture was able to restore the
response to vaccinia-GPE, confirming that
TGF-1 is the major mechanism of inhibition.
Indeed, among subjects initially showing the suppressor phenotype, the
addition of anti-TGF-1 Ab resulted in
responses to HIV-vaccinia exceeding responses to vaccinia control alone
(Fig. 4). Further, in four of eight of the suppressors tested by
peptide stimulation, IFN- secretion was detected, showing an
underlying IFN- response that was suppressed. This suggests that
these individuals have primed CD8+ effector cells
able to respond to HIV with IFN- production. This was confirmed by
demonstrating the inverse relationship between
TGF-1 and IFN- produced by the
same cultures (Fig. 3B). We propose that
inhibition of T cell responses in many HIV+
individuals may result from the specific secretion of
TGF-1, a well-described broadly suppressive
immunomodulatory molecule. It is even more important that different
CD8+ cells (Fig. 5D) seem to produce
TGF-1 and IFN-, thereby raising the
possibility of TGF-1+ cells
being regulatory cells corresponding to Th3 (44). This
provides a rational explanation of the nonspecific lack of immune
responses often observed in HIV+ individuals
before the final drop in CD4+ cells
(45).
We attempted to examine the effects of
TGF-1 production on clinical status. However,
the small number of subjects coupled with a large number of confounding
treatment differences made meaningful comparison of differences
impossible. We emphasize that the study was not designed with
sufficient power to investigate the relationship between
TGF-1 production and clinical status. We are
currently planning an appropriately powered study.
It is also noted in this study that most of the
TGF-1 was produced by the
CD8+ cells in these patients (Figs. 5, A and B) and different cells respond to
TGF-1 and IFN- (Fig. 5D). This
is important because most CTL dysfunctions are more pronounced in
advanced disease when CD8+ cells are abundant
(45). Indeed, when the percentage of
CD3+/CD8+/CD69+/IFN-+
cells were plotted against the gated
CD3+/CD8+ cells, there was
a negative correlation (r2 = 0.9122). A
similar plot with gated
CD3+/CD4+ cells showed a
positive correlation (data not shown). This indicates that the lower
the CD4 count, the more likely the CD8+ cells are
to produce TGF-1 or vice versa. One possible
interpretation is that TGF-1 production
represents a default pathway of CD8+ cells
repeatedly stimulated in the absence of CD4 help.
We were surprised to see the high frequency of
CD8+ cells producing
TGF-1. The frequency is not outside the range
of response to virus infection because in some viral responses, up to
50–70% of the CD8+ T cells can be directed at a
single epitope, and in HIV, a single tetramer can stain up to 10% of
the CD8+ T cells (46, 47, 48). An
alternative explanation is that a smaller number of
CD8+ T cells may have responded and produced
TGF-1 and that TGF-1
induced TGF-1 secretion by other cells.
TGF- has been reported to induce its own secretion in non-T cells
(49).
It is important to note that while the secretion of
TGF-1 is dependent on HIV stimulation, the
effects of TGF-1 are not. We can imagine that
in the lymph nodes of the infected individual there is frequent, if not
constant, stimulation by HIV and the resulting environment with high
levels of TGF-1 would inhibit not only HIV
responses, but also other responses, especially in the local
environment.
A high proportion of individuals in our HIV-infected population (10 of
40) appear to produce high levels of TGF-1 in
response to HIV Ags. These HIV+ donors were
unable to mount an IFN- response to HIV and had suppressed vaccinia
responses in the presence of HIV Ags. Interestingly, most studies of
HIV-specific CTL in HIV+ subjects report the lack
of CTL in a similar proportion (20%) (50).
Given the high prevalence of TGF-1 mediated
suppression of T cell responses in the HIV-infected population, it is
important to consider the potential clinical implications of these
observations. The importance of TGF-1-mediated
suppression of cellular immunity to disease progression and the result
of successful antiretroviral treatment should be explored.
Unfortunately, our current sample size is too small and heterogeneous
for useful analysis. Furthermore, gaining a better understanding
of this phenomenon could have broad implications for HIV immunotherapy
because it is possible that exposure (or re-exposure) to HIV Ags could
elicit nonspecific suppression in either HIV- or
HIV+ individuals. The tendency of particular
immunization protocols to elicit TGF-1
responses in HIV- subjects could prove important
to efficacy in conventional prophylactic vaccine trials and should be
monitored. Similarly, augmentation of TGF- responses in treated
HIV+ individuals could impede the
success of structured treatment interruption and therapeutic
vaccination strategies currently under investigation
(51).
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Jeffery A. Frelinger, Department of Microbiology and Immunology, University of North Carolina, CB#7290 MEJ, Chapel Hill, NC 27599-7290. E-mail address: jfrelin{at}med.unc.edu
3 Abbreviations used in this paper: vaccinia-GPE, VV-ABT 408-6-1, containing clade B HIV-1 IIIB gag, pol, and env; ICC, intracellular cytokine.
Received for publication November 8, 2001. Accepted for publication January 2, 2002.
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