By
§¶
¶
From the * Howard Hughes Medical Institute, Department of Medicine, National Jewish Medical and
Research Center, Denver, Colorado 80206; and the Department of Biochemistry Biophysics and
Genetics, the § Department of Immunology, the
Department of Pharmacology, and the ¶ Department of
Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262
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Abstract |
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Antigen injection into animals causes antigen-specific T cells to become activated and, rapidly
thereafter, die. This antigen-induced death is inhibited by inflammation. To find out how inflammation has this effect, various cytokines were tested for their ability to interfere with the
rapid death of activated T cells. T cells were activated in vivo, isolated, and cultured with the
test reagents. Two groups of cytokines were active, members of the interleukin 2 family and
the interferons (IFNs) and
. This activity of IFN-
/
has not been described previously. It
was due to direct effects of the IFNs on the T cells and was not mediated by induction of a second cytokine such as interleukin 15. IFN-
did not slow the death of activated T cells, and
therefore the activity of IFN-
/
was not mediated only by activation of Stat 1, a protein that
is affected by both classes of IFN. IFN-
/
did not raise the levels of Bcl-2 or Bcl-XL in T cells.
Therefore, their activity was distinct from that of members of the interleukin 2 family or CD28
engagement. Since IFN-
/
are very efficiently generated in response to viral and bacterial infections, these molecules may be among the signals that the immune system uses to prevent activated T cell death during infections.
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Introduction |
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Injection of antigen or superantigen into animals activates specific T cells and allows them to go through several rounds of division. However, these activated cells rapidly go on to die (1). Activation-induced death is caused by several processes in vivo. These probably include engagement of Fas and TNF receptors on the surfaces of activated T cells by their ligands, lack of essential growth factors such as IL-2 or -4 (5), and also other unknown phenomena.
Whatever the causes of activated T cell death, clearly this
phenomenon is not compatible with a productive immune
response since because of it animals frequently contain
fewer antigen-specific T cells several days after exposure to
the antigen than they did before antigen was given. However, it is now known that activation-induced death is inhibited in animals if they are given antigen and an agent
that stimulates inflammation. For example, we have shown that superantigen-specific T cells survive better if superantigen-immunized animals are also exposed to bacterial LPS,
TNF-, or vaccinia virus (9, 10, and Mitchell, T., J. Kappler, and P. Marrack, manuscript submitted for publication). Others have shown that antigen-specific T cells can
be rescued by similar agents (4, 11).
In attempts to find out what makes activated T cells die
or live in animals, we have developed an in vitro system in
which the behavior of the T cells in tissue culture reflects
their fate in vivo. In this system T cells are activated in
animals with antigen or superantigen in the presence or absence of an inflammatory agent. 2 d later the T cells are purified and placed in culture. T cells that have been activated
in animals by exposure to antigens and inflammatory agents
die slowly in culture. T cells activated in animals by antigen
alone and which therefore are destined to die in animals
also die rapidly in culture. We and others have previously
shown that members of the IL-2 family of cytokines prevent this rapid death via a pathway that probably involves Bcl-2 induction (12). In an attempt to find other factors
that may interfere with activated T cell death, we screened
a large number of other cytokines. Of these only one family, the type I IFNs (IFN-/
) were effective. Experiments
with cells from IFN-
/
R-deficient mice showed that, in
vitro, the IFN-
/
acted directly on the T cells and not, as
has been described in vivo (15), via intermediary induction
of IL-15. The IFN-
/
did not act by raising levels of
Bcl-2 or Bcl-XL in the activated cells. We conclude that IFN-
/
can act as survival factors for activated T cells, and that
they act via an intracellular pathway that is not shared by
IFN-
and its receptor and is not the same as that induced
by the IL-2 family or CD28 engagement (12, 16).
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Materials and Methods |
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Mice.
C57BL/10SgSnJ (B10) mice were purchased from The Jackson Laboratory. 129/SvEv animals came from Taconic Farms and IFN-Mouse Manipulations.
T cells were activated in mice by injection of the superantigen staphylococcal enterotoxin B (SEB; Toxin Technology).1 Mice were given 150 µg SEB intravenously in balanced salt solution.Cell Purification and Staining.
T cells were purified on nylon wool columns (26). Intact cells were stained as previously described (27) in balanced salt solution, 2% FBS, 0.1% sodium azide (staining buffer) with biotinylated anti-V
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Cell Culture and Reagents.
Purified T cells were cultured as previously described (9, 14) in the presence or absence of cytokines. Mouse IL-2 and human IL-15 were purchased from R&D Systems. A mixture of mouse IFN-Analysis of Cell Division.
Lymphocyte proliferation in culture was assayed by uptake of [3H]TdR. In brief, cells were cultured at a starting concentration of 3 × 105 cells/150 µl in the wells of 96-well tissue culture plates. 2-3 d later, 1 µCi [3H]TdR was added to each well and the cells were incubated for an additional 6 h before harvest using a 1450 Microbeta Plus liquid scintillation counter (Wallac). Cell division was also analyzed after permeabilization of the cells in 0.3% saponin and addition of 5 µg/ml propidium iodide. The percentages of cells in G1 and G2/S, and with <2 N amounts of DNA were then identified cytofluorographically. ![]() |
Results |
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T cells
that have been activated in animals die rapidly in vivo or in
culture unless their activation occurred in the presence of
an inflammatory agent such as LPS or an adjuvant (1, 9, 10). To find out how inflammation has this effect, we
screened a large number of agents for their ability to prevent the death of T cells activated in vivo and then cultured in vitro (Table I). Many of the agents had no effect in
this assay. Members of two cytokine families, the IL-2 family and the type I IFN (IFN-/
) family, were active. Several groups including ourselves have previously described
the effects of IL-2 family members (12, 29, 30); however, the ability of IFN-
/
to prevent activated T cell
death has not been reported previously.
|
An example of an IFN-/
experiment is shown in Fig. 1.
T cells were activated in vivo by injection of SEB, a superantigen which reacts with T cells bearing members of the
V
8 family in their TCRs, into mice. 2 d later lymph node
T cells were purified and cultured in the presence or absence of IFN-
/
. 1 d later, the percentages of live V
8+
or control V
6+ T cells were measured using either live/
dead gates of the forward versus side scatter bit maps of the
cells or DNA content, as assessed by staining of permeabilized cells with propidium iodide.
The results of both types of assays for dead cells were similar, except that in every case fewer of the cells were alive after culture as defined by forward versus side scatter than as defined by DNA content (Fig. 1). This difference was probably due to the fact that DNA degradation is a relatively late event in apoptosis (31). Because measurement of cell survival by light scatter properties allowed more flexible use of staining reagents and identified dead cells at an earlier stage, this assay was used to define dead cells in the remaining experiments described in this paper. However, in most cases the results were confirmed using DNA content or cell permeability as measures of cell survival.
Fig. 1 shows that <40% of the control V6+ cells died
during overnight culture. In contrast, almost 70% of the
SEB-activated, V
8+ T cells died. Thus, as we have previously described, T cells die more quickly in culture if they
have previously been activated in vivo (9). Culture with
IFN-
/
slightly increased the survival of the resting,
V
6+ T cells in overnight culture, but dramatically prevented the death of the activated, V
8+ T cells (Fig. 1).
The fact that IFN-/
have only a very slight effect on
the rate of death of resting T cells was also demonstrated in
an experiment in which IFN-
/
was titrated. Increasing
doses of IFN-
/
had increasing abilities to promote the
survival of activated T cells and had very little effect on the
survival of resting T cells (Fig. 2). This was not due to absence of IFN-
/
receptors on resting T cells, since, as
shown in Fig. 3, culture in IFN-
/
increased the levels of
class I MHC on resting T cells. For CD4+ T cells, the effects of IFN-
/
on class I expression were less dramatic if
the T cells were resting compared with if they were activated. On the other hand, for CD8+ T cells the dose-
response curve was almost exactly the same whether or not
the cells were activated.
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IFN-/
increased the survival of both CD4+ and
CD8+ T cells, providing the cells were activated. Thus, as
shown in Fig. 2, increasing doses of IFN-
/
kept increasing percentages of CD4 or CD8+ SEB-activated, V
8+ T
cells alive. However, the effects of IFN-
/
on cell survival were consistently more pronounced for CD8+ T cells
than for CD4+ T cells. This was not because CD4+-activated T cells are intrinisically less sensitive to IFN-
/
than are CD8+-activated cells since, as shown in Fig. 3,
culture in increasing concentrations of IFN-
/
raised class
I MHC expression on both CD4+- and CD8+-activated T
cells. In fact, class I was induced to higher levels on activated CD4+ cells than on CD8+ cells.
The extent to which activated T cells died, and therefore
to which IFN-/
rescued them, varied with time in culture and strain of mice. For example, the cultures shown in
Fig. 2 were incubated for 20 h and those shown in Fig. 4
were incubated for 24 h, and there was more extensive
death in the absence of, and proportional rescue in the
presence of, IFN-
/
in the latter experiments than in the
former. The mouse strain from which the activated T cells were derived also affected rates of death in vitro. Thus, the activated T cells from 129 mice (Table II) died more slowly
than those from C57Bl/10 mice, a difference between 129 and C57Bl/10 T cells that we have consistently observed in
many experiments.
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|
IFN- is distinguished from the large family of IFN-
's
by sequence differences. However, both IFN-
and IFN-
are thought to act via the same heterodimeric receptor
(IFN-
/
R; references 34, 35). Since both IFN-
and
IFN-
act on the same receptor, we expected that each
type of protein would have the same effect on T cells as the
mixture of the two that was used for the experiments shown thus far in this paper. To find out whether this was
so, T cells were activated in vivo with SEB, harvested and
purified 2 d later, and cultured in various concentrations of
IFN-
or IFN-
. As shown in Fig. 4, both kinds of IFN
increased the life expectancy of activated T cells in vitro;
however, IFN-
was somewhat more active than the
IFN-
protein tested. Whether this represents a consistent
difference between IFN-
and all the members of the IFN-
family awaits further investigation.
In summary, these experiments show that IFN- and
IFN-
promote the survival of activated T cells in vitro.
IFN-
/
has little or no effect on the survival of resting T
cells, despite the fact that these cells can respond to IFN-
/
by raising their surface levels of class I strongly on CD8+ T
cells and to a lesser extent on CD4+ cells.
Tough et al. recently reported that IFN-/
make CD44hi CD8+ T cells divide in
vivo (36). Subsequently this group showed that the IFNs
probably do not act directly, but rather indirectly by induction of IL-15, which in turn affects the T cells (15). To find
out whether IFN-
/
were acting in a similarly indirect manner in vitro, we set up cultures containing mixtures
of SEB-activated T cells from normal and IFN-
/
R-deficient mice. The normal T cells were distinguished from the
IFN-
/
R-deficient cells by labeling the latter with CFSE.
IFN-
/
increased the survival of the T cells from normal
mice but had no effect on T cells lacking IFN-
/
Rs (Table
II), even though the two types of cells were cultured together. Toxicity due to CFSE labeling did not contribute to this since identical results were obtained in mixed cultures in which the normal T cells were labeled with CFSE
and the IFN-
/
R cells were unlabeled. Thus, IFN-
/
were acting directly on T cells in culture. Of course under
some circumstances they may also act indirectly via induction of cytokines such as IL-15, but these effects were not
manifest in our cultures of purified T cells.
IL-15 stimulates the proliferation of activated T cells but
IFN-/
do not (37). To confirm the idea that, in the
experiments described in this paper, IFN-
/
were not
acting via IL-15, we tested their effects on T cell proliferation. T cells were isolated from mice given SEB 2 d previously and cultured in the presence of different concentrations of IFN-
/
or as controls without added cytokines
or with IL-2. The cells cultured alone did not proliferate.
They divided vigorously in response to IL-2. Such cells also
divided in response to IL-15 (data not shown). The cells
did not divide at all in response to IFN-
/
(Fig. 5). The same conclusion was drawn from experiments in which T
cells were labeled with CFSE and cultured in the presence
or absence of IFN-
/
or IL-15. After 24 h, CFSE staining
showed that, of the activated CD8+ T cells that were still
alive, 8.9 ± 1.2% had divided if the cells were cultured
alone, whereas 5.5 ± 0.6 or 15.5 ± 0.74% had divided if
the cells were cultured in IFN-
/
or IL-15, respectively. Likewise, counts of total cell yield showed that there was
no difference in the number of T cells per culture after 24 h
of incubation in the presence or absence of IFN-
/
. In
one experiment, 6.1 ± 0.5 × 105 cells were recovered
from cultures incubated for 24 h without IFN-
/
, and
5.4 ± 0.3 × 105 cells were recovered from cultures incubated with 3,333 U/ml IFN-
/
. Hence, IFN-
/
do not
cause activated T cells to divide.
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These results showed that IFN-/
were not acting via
induction of IL-15, since they did not stimulate activated T
cell division. Also, IFN-
/
did not cause a higher percentage of activated T cells to survive culture because they
stimulated T cells to proliferate and hence overgrow dying
cells. Rather, IFN-
/
promoted the survival of previously activated T cells.
IFN-/
share many biological effects with IFN-
, even
though the two types of IFN act via different receptors (33,
34, 40). However, IFN-
did not prevent the deaths of activated T cells. Thus, as shown in Fig. 2, incubation with
various concentrations of IFN-
had no effect on the survival of CD4+ or CD8+ activated or resting T cells. This
was not because these cells did not bear receptors for IFN-
since, as shown in Fig. 3, incubation with IFN-
did raise
class I MHC levels on these T cells, albeit with a bell-shaped dose-response curve.
It was surprising that IFN- did not have the same activity
as IFN-
/
. Although the two types of IFNs act through
different receptors (34, 35, 41), they share many intracellular
signaling pathways and therefore have many similar effects
on cells (42, 43). The fact that the two types of IFNs differ in
this assay shows that IFN-
/
prevents T cell death via an
intracellular pathway that is not triggered by the IFN-
receptor. Therefore, although Stat1 activation may be required
for the effects described here (42), it is not sufficient.
Other cytokines, including
IL-15, that protect activated T cells against death raise the
amounts of Bcl-2 in the activated cells (12, 14, 29). If
IFN-/
were acting via IL-15, or by a route similar to
that induced by IL-2 family members, then they should
also raise Bcl-2 in the T cells. To check this, T cells were
isolated from mice primed 2 d previously with SEB and stained for Bcl-2 content. At the time of isolation the activated, V
8+ T cells contained about half of the amount of
Bcl-2/cell that resting, V
6+ T cells did (footnote to Table
III). This lowered level of Bcl2 may contribute to the increased rate of death of the activated cells.
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The cells were then cultured in the presence or absence
of IFN-/
or IL-2 or IL-15. As shown in Table III, all
three of these cytokines increased the survival rate of the
activated T cells. The effects of IL-2 and IL-15 were more
profound than those of IFN-
/
.
T cells cultured alone contained less Bcl-2 per cell after
culture than before. Activated, V8+ T cells cultured
alone continued to contain less Bcl-2 per cell than resting,
V
6+ T cells did. This was also true for activated V
8+ T
cells cultured in IFN-
/
, even though these cells had a
markedly improved survival rate over that of activated cells
cultured alone. The amounts of Bcl-2 in the activated
V
8+ T cells did not fall so much or were maintained by
culture in IL-2 or IL-15.
As we have previously described, the high concentrations of IL-2 or IL-15 used in this experiment also increased the survival rate of the resting T cells (Table III, reference 14, and data not shown). Commensurate with this, the IL-2 family members helped to maintain Bcl-2 levels to a very small extent in CD4+ T cells and much more markedly in the CD8+ T cells.
Bcl-X can also promote the survival of T cells (12, 13,
20, 24). Therefore we tested the effects of culture with
IFN-/
on Bcl-X levels. V
8+ T cells were activated in
vivo using SEB and isolated 2 d later as described above. At
the time they were removed from the animals, the activated, V
8+ T cells contained ~50% more Bcl-X per cell
than did the resting T cells (footnote to Table IV). This
was probably due to induction of Bcl-X in the activated
cells by CD28/B7 engagement (12, 13, 20, 24). After 1 d
in culture, the levels of Bcl-X in the activated, V
8+ and
resting, V
6+ T cells were the same. These levels were unaffected by culture in IL-2, raised slightly (especially in the
CD8+ T cells) by culture in IL-15, and completely unaffected by culture in IFN-
/
(Table IV). Although these
results do not distinguish between the two forms of Bcl-X,
Bcl-XL and Bcl-XS, they do suggest that levels of either form
are not affected by IFN-
/
.
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These results demonstrate that the rescuing activity of
IFN-/
does not depend upon induction of either Bcl-2
or Bcl-X in activated T cells. Thus, the means whereby
IFN-
/
protect activated T cells against death must be
different than those used in protection by IL-2 family
members or by CD28 engagement.
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Discussion |
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Experiments described elsewhere show that T cells that
have been activated in vivo in the absence of adjuvant die
rapidly in animals or after isolation and culture (1, 9).
In vitro, a number of cytokines prevent the deaths of these
activated cells. Previously, we and others have shown that
members of the IL-2 family do this very effectively (12,
29). In this paper we show that IFN-/
are also active.
The IL-2 family and IFN-/
do not act in the same
way. IL-2 and its relatives all have the ability to induce Bcl-2
synthesis in responsive T cells (12, 29). It is likely that it
is this increase in Bcl-2 which increases the life expectancy
of the cells. Members of the IL-2 family also have, to varying degrees, the ability to induce proliferation of the responding T cells. IL-2 and IL-15 are particularly effective
in this regard, and IL-4 and IL-7 are less so (14). On the
other hand, the IFN-
/
family does not act in any of
these ways. IFN-
/
do not increase Bcl-2 levels in T
cells. IFN-
/
also do not stimulate T cell division. In fact,
IFN-
/
are often thought to be inhibitors rather than stimulators of proliferation (38).
Recently, Tough et al. have studied the effects of IFN-/
on T cells. They showed that induction of IFN-
/
in animals caused a subset of what appear to be activated or
memory CD8+ T cells to divide (36). Later experiments
showed that this was probably due to the ability of IFN-
/
to induce IL-15 production by cells such as macrophages
(15). We do not think that the IFN-
/
is acting in such a
way in the experiments described here. Experiments with
mixtures of wild-type and IFN-
/
R-deficient cells showed
that IFN-
/
were acting directly on the T cells and not indirectly via induction of some other molecule. Also, as discussed above, apart from their common ability to prevent the death of activated T cells, IFN-
/
and IL-15 affect T
cells in completely different ways.
The IFN-/
were not as efficient in preventing the
deaths of activated T cells as the IL-2-related cytokines
were. This was not simply because the IL-2 family members
induced cell division and thus overgrowth of dead cells by
dividing T cells. Rather, at optimal concentrations IL-2 like
cytokines appeared to prevent activated T cell death almost
entirely, whereas the IFN-
/
simply slowed the process.
The IFN-/
do not act via increased induction of another survival protein, Bcl-X. Therefore, their effects are
probably not due to induction of members of the B7 family
and increased engagement of CD28 on T cells (19).
IFN- did not share the ability of IFN-
/
to inhibit
the death of activated T cells. This was not because activated T cells lacked receptors for IFN-
, since IFN-
increased class I MHC expression on such cells. Thus, the
rescuing activity of IFN-
/
must involve a feature of
signaling of the IFN-
/
R that is not shared with that of
the IFN-
R. There are several candidates for differential
factors. Although both receptors activate Stat1, only the
IFN-
/
R activates Stat2 and Stat4 and creates the heterodimeric transcription factor, ISGF3 (38, 44). In addition, in T cells, the engaged IFN-
/
R is associated with
several proteins (p54lck, CD45, and Zap70) known to be
important in T cell activation (42). Perhaps one or more of
these properties of the IFN-
/
R distinguishes signaling
by IFN-
/
from that of IFN-
to T cells.
The fact that the IFN-/
prevent activated T cell death
has considerable implications. It may contribute to the large
numbers of antigen-specific and nonspecific T cells that appear during virus infections (47). It may also account
for the long suspected association between virus infections
and induction of autoimmune diseases (51).
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Footnotes |
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Address correspondence to Philippa Marrack, Howard Hughes Medical Institute, National Jewish Medical and Research Center, Goodman Bldg., 5th Floor, 1400 Jackson St., Denver, CO 80206. Phone: 303-398-1322; Fax: 303-398-1396; E-mail: marrackp{at}njc.org
Received for publication 17 August 1998 and in revised form 14 October 1998.
1 Abbreviations used in this paper: CFSE, carboxyfluorescein diacetate succinimidyl ester; CY, cychrome; SEB, staphylococcal enterotoxin B.The authors thank Drs. Schreiber and Aguet for their generous gift of breeding pairs of IFN-/
R-deficient mice.
This work was supported in part by United States Public Health Service grants AI17134, AI18785, and AI22295.
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References |
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1. | Webb, S., C. Morris, and J. Sprent. 1990. Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity. Cell. 63: 1249-1256 [Medline]. |
2. |
Kawabe, Y., and
A. Ochi.
1991.
Programmed cell death and
extrathymic reduction of V![]() |
3. |
McCormack, J.E.,
J.E. Callahan,
J. Kappler, and
P. Marrack.
1993.
Profound deletion of mature T cells in vivo by chronic
exposure to exogenous superantigen.
J. Immunol.
150:
3785-3792
|
4. | Kearney, E.R., K.A. Pape, D.Y. Loh, and M.K. Jenkins. 1994. Visualization of peptide-specific immunity and peripheral tolerance induction in vivo. Immunity. 1: 327-339 [Medline]. |
5. | Duke, R.C.. 1986. IL-2 addiction: withdrawal of growth factor activates a suicide program in dependent T cells. Lymphokine Res. 5: 289-299 [Medline]. |
6. | Debatin, K.M., C.K. Goldmann, R. Bamford, T.A. Waldmann, and P.H. Krammer. 1990. Monoclonal antibody- mediated apoptosis in adult T-cell leukaemia. Lancet. 335: 497-500 [Medline]. |
7. | Van Parijs, L., A. Ibraghimov, and A.K. Abbas. 1996. The roles of costimulation and fas in T cell apoptosis and peripheral tolerance. Immunity. 4: 321-328 [Medline]. |
8. | Sytwu, H.K., R.S. Liblau, and H.O. McDevitt. 1996. The roles of Fas/Apo-1 (CD95) and TNF in antigen-induced programmed cell death in T cell receptor transgenic mice. Immunity. 5: 17-30 [Medline]. |
9. | Vella, A.T., J.E. McCormack, P.S. Linsley, J.W. Kappler, and P. Marrack. 1995. Lipopolysaccharide interferes with the induction of peripheral T cell tolerance. Immunity. 2: 261-270 [Medline]. |
10. | Vella, A.T., T. Mitchell, B. Groth, P.S. Linsley, J.M. Green, C.B. Thompson, J.W. Kappler, and P. Marrack. 1997. CD28 engagement and proinflammatory cytokines contribute to T cell expansion and long term survival in vivo. J. Immunol. 158: 4714-4720 [Abstract]. |
11. | Chiller, J.M., and W.O. Weigle. 1973. Termination of tolerance to human gamma globulin in mice by antigen and bacterial lipopolysaccharide (endotoxin). J. Exp. Med. 137: 740-750 [Medline]. |
12. |
Akbar, A.N.,
N.J. Bothwick,
R.G. Wickremasinghe,
P. Panayiotidis,
D. Pilling,
M. Bofill,
S. Krajewski,
J.C. Reed, and
M. Salmon.
1996.
Interleukin-2 receptor common ![]() |
13. | Mueller, D.L., S. Seiffert, W. Fang, and T.W. Behrens. 1996. Differential regulation of bcl-2 and bcl-x by CD3, CD28 and the IL-2 receptor in cloned CD4+ helper T cells. A model for the long term survival of memory cells. J. Immunol. 156: 1764-1771 [Abstract]. |
14. |
Vella, A.T.,
S. Dow,
T.A. Potter,
J. Kappler, and
P. Marrack.
1998.
Cytokine induced survival of activated T cells in vitro
and in vivo.
Proc. Natl. Acad. Sci. USA.
95:
3810-3815
|
15. | Zhang, X., S. Sun, I. Hwang, D.F. Tough, and J. Sprent. 1998. Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity. 8: 591-600 [Medline]. |
16. | Veis, D.J., C.M. Sorenson, J.R. Shutter, and S.J. Korsmeyer. 1993. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell. 75: 229-240 [Medline]. |
17. |
Veis, D.J.,
C.L. Stentman,
E.A. Bach, and
S.J. Korsmeyer.
1993.
Expression of the Bcl-2 protein in murine and human
thymocytes and in peripheral T lymphocytes.
J. Immunol.
151:
2546-2554
|
18. |
Nakayama, K.,
K.-I. Nakayama,
I. Negishi,
K. Kuida,
H. Sawa, and
D.Y. Loh.
1994.
Targeted disruption of Bcl-2![]() ![]() |
19. | Shahinian, A., K. Pfeffer, K.P. Lee, T.M. Kundig, K. Kishihara, A. Wakeham, K. Kawai, P.S. Ohashi, C.B. Thompson, and T.W. Mak. 1993. Differential T cell costimulatory requirements in CD28-deficient mice. Science. 261: 609-612 [Medline]. |
20. | Chao, D.T., G.P. Linette, L.H. Boise, L.S. White, C.B. Thompson, and S.J. Korsmeyer. 1995. Bcl-XL and Bcl-2 repress a common pathway of cell death. J. Exp. Med. 182: 821-828 [Abstract]. |
21. | Boise, L.H., A.J. Minn, P.J. Noel, C.H. June, M.A. Accavitti, T. Lindsten, and C.B. Thompson. 1995. CD28 stimulation can enhance T cell survival by inducing expression of Bcl-XL. Immunity. 3: 87-98 [Medline]. |
22. | Sperling, A.I., J.A. Auger, B.D. Ehst, I.C. Rulifson, C.B. Thompson, and J.A. Bluestone. 1996. CD28/B7 interactions deliver a unique signal to naïve T cells that regulates cell survival but not early proliferation. J. Immunol. 157: 3909-3917 [Abstract]. |
23. | Radvanzi, L.G., Y. Shi, H. Vaziri, A. Sharma, R. Dhala, G.B. Mills, and R.G. Miller. 1996. CD28 costimulation inhibits TCR-induced apoptosis during a primary immune response. J. Immunol. 156: 1788-1798 [Abstract]. |
24. | Noel, P.J., L.H. Boise, J.M. Green, and C.B. Thompson. 1996. CD28 costimulation prevents cell death during primary T cell activation. J. Immunol. 157: 636-642 [Abstract]. |
25. | Muller, U., U. Steinhoff, L.F.L. Reis, S. Hemmi, J. Pavlovic, R.M. Zinkernagel, and M.A. Aguet. 1994. Functional role of type I and type II interferons in antiviral defense. Science. 261: 1918-1921 . |
26. | Julius, M.H., E. Simpson, and L. Herzenberg. 1973. A rapid method for the isolation of functional thymus-derived murine T lymphocytes. Eur. J. Immunol. 3: 645-650 [Medline]. |
27. | Scherer, M.T., L. Ignatowicz, A. Pullen, J. Kappler, and P. Marrack. 1995. The use of Mtv mice to evaluate the effects of endogenous viral superantigens on the T cell repertoire. J. Exp. Med. 182: 1493-1504 [Abstract]. |
28. | Weston, S.A., and C.R. Parish. 1990. New fluorescent dyes for lymphocyte migration studies. Analysis by flow cytometry and fluorescence microscopy. J. Immunol. Methods. 133: 87-97 [Medline]. |
29. | Kaneko, S., N. Suzuki, H. Koizumi, S. Yamamoto, and T. Sakane. 1997. Rescue by cytokines of apoptotic cell death induced by IL-2 deprivation of human antigen-specific T cell clones. Clin. Exp. Immunol. 109: 185-193 [Medline]. |
30. | Maraskovsky, E., M. Teepe, P.J. Morrissey, S. Braddy, R.E. Miller, D.H. Lynch, and J.J. Peschon. 1996. Impaired survival and proliferation in IL-7 receptor deficient peripheral T cells. J. Immunol. 157: 5315-5323 [Abstract]. |
31. | Swat, W., L. Ignatowicz, and P. Kisielow. 1991. Detection of apoptosis of immature CD4+8+ thymocytes by flow cytometry. J. Immunol. Methods. 137: 79-87 [Medline]. |
32. | Wesselborg, S., and D. Kabelitz. 1993. Activation-driven death of human T cell clones: time course kinetics of the induction of cell shrinkage, DNA fragmentation, and cell death. Cell. Immunol. 148: 234-241 [Medline]. |
33. | Hotz, M.A., J. Gong, F. Traganos, and Z. Darzynkiewicz. 1994. Flow cytometric detection of apoptosis: comparison of the assay of in situ DNA degradation and chromatin changes. Cytometry. 15: 237-244 [Medline]. |
34. |
Novick, D.,
B. Cohen, and
M. Rubenstein.
1994.
The human ![]() ![]() |
35. |
Uze, G.,
G. Lutfalla, and
I. Gresser.
1990.
Genetic transfer of
a functional interferon ![]() |
36. | Tough, D.F., P. Borrow, and J. Sprent. 1996. Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science. 272: 1947-1950 [Abstract]. |
37. | Grabstein, K.H., J. Eisenman, K. Shanebeck, C. Rauch Sr, and inivasan, V. Fung, C. Beers, J. Richardson, M.A. Schoenborn, M. Ahdieh, et al., . 1994. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science. 264: 965-968 [Medline]. |
38. | Fradelizi, D., and I. Gresser. 1982. Interferon inhibits the generation of allospecific suppressor T lymphocytes. J. Exp. Med. 155: 1610-1622 [Abstract]. |
39. | Puri, R.K., W.D. Travis, and S.A. Rosenberg. 1990. In vivo administration of interferon alpha and interleukin 2 induces proliferation of lymphoid cells in the organs of mice. Cancer Res. 50: 5543-5550 [Abstract]. |
40. | Petricoin, E.F. III, S. Ito, B.L. Williams, S. Audet, L.F. Stancato, A. Gamero, K. Clouse, P. Grimley, A. Weiss, J. Beeler, et al . 1997. Antiproliferative action of interferon alpha requires components of T cell receptor signalling. Nature. 390: 629-632 [Medline]. |
41. | Aguet, M., Z. Dembic, and G. Merlin. 1988. Molecular cloning and expression of the human interferon-gamma receptor. Cell. 55: 273-280 [Medline]. |
42. | Shual, K., A. Ziemiecki, A.F. Wilks, A.G. Harpur, H.B. Sadowski, M.Z. Gilman, and J.E. Darnell. 1993. Polypeptide signalling to the nucleus through tyrosine phosphorylation of Jak and Stat proteins. Nature. 366: 580-583 [Medline]. |
43. | Ihle, J.N.. 1995. The Janus protein tyrosine kinase family and its role in cytokine signaling. Adv. Immunol. 60: 1-35 [Medline]. |
44. | Leung, S., S.A. Qureshi, I.M. Kerr, J.E. Darnell, and G.R. Stark. 1995. Role of Stat2 in the alpha interferon signaling pathway. Mol. Cell. Biol. 15: 1312-1317 [Abstract]. |
45. | Cho, S.S., C.M. Bacon, C. Sudarshan, R.C. Rees, D. Finbloom, R. Pine, and J.J. O'Shea. 1996. Activation of STAT4 by IL-12 and IFN-alpha: evidence for the involvement of ligand-induced tyrosine and serine phosphorylation. J. Immunol. 157: 4781-4790 [Abstract]. |
46. | Bhattacharya, S., R. Eckner, S. Grossman, E. Oldread, Z.D. Arany, A. Andrea, and D.M. Livingstone. 1996. Cooperation of Stat2 and p300/CBP in signalling induced by interferon alpha. Nature. 383: 344-347 [Medline]. |
47. |
Yang, H., and
R.M. Welsh.
1986.
Induction of alloreactive
cytotoxic T cells by acute virus infection of mice.
J. Immunol.
136:
1186-1193
|
48. |
Tripp, R.A.,
S. Hou,
A. McMickle,
J. Houston, and
P.C. Dougherty.
1995.
Recruitment and proliferation of CD8+
T cells in respiratory viral infections.
J. Immunol.
154:
6013-6021
|
49. | Butz, E.A., and M.J. Bevan. 1998. Massive expansion of antigen-specific CD8+ T cells during an acute viral infection. Immunity. 8: 167-175 [Medline]. |
50. | Murali-Krishna, K., J.D. Altman, M. Suresh, D.J.D. Sourdive, A.J. Zajac, J.D. Miller, J. Slansky, and R. Ahmed. 1998. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity. 8: 177-187 [Medline]. |
51. | Dahlquist, G.G.. 1997. Viruses and other perinatal exposures as initiating events for beta-cell destruction. Ann. Med. 29: 413-417 [Medline]. |
52. | Miller, S.D., C.L. Vanderlugt, W.S. Begolka, W. Pao, R.L. Yauch, K.L. Neville, D. Katz, Y. Levy, A. Carrizosa, and B.S. Kim. 1997. Persistent infection with Theiler's virus leads to CNS autoimmunity via epitope spreading. Nat. Med. 3: 1133-1145 [Medline]. |
53. | Phillips, P.E.. 1997. Viral arthritis. Curr. Opin. Rheumatol. 9: 337-344 [Medline]. |