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-Dependent Pathway Controls Stimulation of Memory Phenotype CD8+ T Cell Turnover In Vivo by IL-12, IL-18, and IFN-1
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Edward Jenner Institute for Vaccine Research, Compton, Newbury, Berkshire, United Kingdom; and
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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rather
than IFN-I dependent and is mediated by at least three cytokines,
IL-12, IL-18, and IFN-. As for IFN-I, these three cytokines are
nonstimulatory for purified T cells and under in vivo conditions
probably act via production of IL-15. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The most straightforward explanation for the observed rapid turnover of memory T cells is that cell division is occurring in response to antigenic stimulation. However, it is clear that memory T cells can persist long term in the absence of specific Ag (11, 12, 13, 14, 15, 16). Furthermore, it has been shown that memory CD8+ T cells divide after adoptive transfer into recipient mice in the absence of Ag (8, 17) and also after adoptive transfer into MHC class I-deficient mice (16, 17). The latter result strongly suggests that memory T cells can be driven to divide by signals delivered independently of TCR-MHC interactions. Consistent with this, recent studies have shown that certain cytokines can induce bystander proliferation of memory phenotype T cells in vivo (18, 19).
Cytokine-induced bystander proliferation is largely restricted to cells
having a memory phenotype. Thus, injection of either type I IFN
(IFN-I)3 or inducers
of IFN-I into normal mice induced a marked increase in
CD44high CD8+ T cell
proliferation, whereas little if any increase in proliferation was
observed for naive phenotype CD8+ T cells
(18); a recent study has shown that injection of
poly(I:C), an inducer of IFN-I, also stimulates bystander proliferation
of memory but not naive phenotype CD4+ T cells
(20). Importantly, CD44high
CD8+ T cells divided in vivo in response to IFN-I
after adoptive transfer to
2-microglobulin-/-
mice, indicating that TCR stimulation was likely not involved.
Proliferation in response to IFN-I implies that bystander proliferation
of CD8+ memory T cells might be a frequent
occurrence, since rapid induction of IFN-I is a common response to
infection. Indeed, marked proliferation of
CD44high CD8+ T cells
occurs after injection of poly(I:C) (18), LPS
(21), or CpG DNA (22, 23); these compounds
are powerful inducers of IFN-I in vivo. However, experiments in mice
lacking a functional IFN-I receptor (IFN-IR-/-)
suggested that IFN-I might not be unique in its ability to induce
bystander proliferation. In these mice, memory phenotype
CD8+ T cells failed to proliferate in response to
a low dose of LPS, but did so after injection of a higher dose. An
obvious possibility is that the higher dose of LPS induced additional
cytokines that were also able to stimulate
CD44high CD8+ T cells.
Subsequent work showed that IL-15 was one such cytokine, as injection
of IL-15 into mice stimulated potent and selective proliferation of
CD44high CD8+ T cells
(19). Furthermore, it has been reported that
IFN-I-independent bystander proliferation of
CD44high CD8+ T cells also
occurs after injection of the NKT cell stimulator
-galactosylceramide (20). In this study, injection of
neutralizing anti-IFN- Ab failed to inhibit
-galactosylceramide-induced proliferation of
CD44high CD8+ T cells in
the liver. There was, however, a partial reduction in the bystander
response in IL-12-deficient mice also injected with anti-IFN-
(but not in IL-12-deficient mice themselves), suggesting a possible
role for IFN-.
Thus, although it has been demonstrated that memory phenotype
CD8+ T cells are sensitive to bystander
stimulation in vivo, the range of infection-induced cytokines capable
of inducing proliferation is not known. In this paper, we report that
three additional cytokines, IL-12, IL-18, and IFN-, share the
capacity of IFN-I to induce selective proliferation of
CD44high CD8+ T cells in
vivo but not in vitro. In contrast to IFN-I, however, these three
cytokines induce T cell proliferation in vivo by an IFN--dependent
pathway.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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C57BL/6 (B6) mice were purchased from either the rodent breeding
colony at The Scripps Research Institute, the specific pathogen-free
unit at the Institute for Animal Health (Compton, U.K.), or The Jackson
Laboratory (Bar Harbor, ME). 129/SvEvTacfBR (129) mice were purchased
from Taconic Farms (Germantown, NY). 129 background mice defective in
IFN-IR function (IFN-IR-/-) (24)
were originally purchased from B&K Universal (North Humberside, U.K.)
and were maintained and bred in the animal facility at The Scripps
Research Institute. IFN--deficient
(IFN--/-) mice were purchased from The
Jackson Laboratory or the specific pathogen-free unit at the Institute
for Animal Health. C3H/HeJ and C3H/HeOuJ mice were purchased from The
Jackson Laboratory.
Cytokines and injection
Recombinant murine IL-12 used was either that provided as a gift
from Genetics Institute (Cambridge, MA) or that purchased from R&D
Systems (Minneapolis, MN). Recombinant mouse IFN- and recombinant
human IL-15 were purchased from R&D Systems. IL-18 was purchased from
BioSource International (Camarillo, CA). The specified doses of
cytokines were injected into mice i.v. as indicated.
Treatment of mice with bromodeoxyuridine (BrdU)
Mice were given BrdU (Sigma, St. Louis, MO) in their drinking water at a concentration of 0.8 mg/ml. BrdU administration was started immediately after injections and mice were sacrificed 3 days later. BrdU was dissolved in sterile water and changed daily.
In vitro culture of T cells
CD8+ T cells were purified by staining total LN or spleen cells with anti-CD8-PE (Life Technologies, Grand Island, NY) followed by cell sorting on a MoFlo flow cytometer (Cytomation, Fort Collins, CO). Sorted cells were resuspended in complete medium (RPMI 1640 + GlutaMAX I (Life Technologies) supplemented with 10% FCS, 5% NCTC-135 (Life Technologies), 5 x 10-8 M 2-ME (Sigma), 250 µg/ml gentamicin (Life Technologies), and 50 U/ml penicillin/streptomycin (Life Technologies)), and plated at 1 x 106 cells/ml (1 ml/well) in 24-well plates. Cells were cultured in medium alone, or medium supplemented with recombinant murine IL-12, recombinant murine IL-18, or recombinant human IL-15 as indicated. BrdU was added to wells at 12.5 µg/ml from the beginning of culture, and cells were assayed 40 or 72 h later as indicated. Harvested cells were depleted of dead cells by centrifugation over Histopaque-1083 (Sigma) before staining.
Monoclonal Abs and flow cytometry
mAbs used for cell surface staining were the following: anti-CD8-PE, anti-CD4-PE (Life Technologies), anti-CD44-biotin (IM7.8.1), anti-Ly-6C-biotin (PharMingen, San Diego, CA), anti-CD4-Cy-5 (GK1.5), and anti-CD8-Cy-5. Anti-CD4-Cy-5 was prepared using a kit from Amersham Life Science (Arlington Heights, IL). Anti-CD8-Cy-5 was either purchased from Caltag (Burlingame, CA) or prepared as for anti-CD4-Cy-5. Biotinylated Abs were detected with streptavidin-Red670 (Life Technologies).
After surface staining, BrdU labeling was assessed with anti-BrdU-FITC (Becton Dickinson, Mountain View, CA) as described elsewhere (4). Stained cells were analyzed on either FACSCan or FACSCalibur flow cytometers (Becton Dickinson).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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To determine the effect of IL-12 on T cell turnover, graded doses
of recombinant murine IL-12 were injected i.v. into B6 mice and the
recipients were given BrdU in the drinking water for 3 days (Fig. 1
, A–D). Injection of IL-12
stimulated a marked proliferation of memory phenotype
CD44high CD8+ T cells, with
the percentage of BrdU-labeled cells increasing in a dose-dependent
manner; this was true in both LN and spleen (Fig. 1, A and
B). In contrast to CD44high
CD8+ T cells, IL-12 had no effect on the BrdU
labeling of naive phenotype CD44low
CD8+ T cells. Similarly, injection of IL-12
induced minimal proliferation among LN CD4+ T
cells, although a small increase in BrdU labeling was observed at the
highest dose of IL-12 injected for CD44high cells
only (Fig. 1C). Of note, significant proliferation of
splenic CD44high CD4+ cells
was observed after injection of IL-12, but such stimulation was largely
restricted to a subset of NK1.1+ cells (data not
shown). How these cells are stimulated by IL-12 will be the subject of
another publication. The remainder of this paper will focus on the
effects of IL-12 on memory phenotype CD8+ T
cells.
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E) or spleen (data not
shown), BrdU incorporation in vitro was virtually undetectable, both
for CD44high and CD44low
CD8+ cells. By contrast, strong stimulation of
CD44high (but not CD44low)
CD8+ cells occurred following addition of IL-15.
These results therefore suggest that the in vivo induction of
proliferation of CD44high
CD8+ cells by IL-12 was mediated by indirect
mechanisms rather than direct stimulation of the T cells. Role of IFN-I in IL-12-induced turnover
In addition to inducing T cell proliferation, in vivo injection of
IL-12 induced CD8+ T cells to up-regulate Ly-6C
(Fig. 1D). Since Ly-6C was reported to be selectively
up-regulated by IFN-I (25), this result suggested that
IL-12 induced synthesis of IFN-I. Hence, bearing in mind that IFN-I
elicits strong proliferation of CD44high
CD8+ T cell turnover in vivo (18),
stimulation of these cells by IL-12 could be mediated via IFN-I. To
test this possibility, IL-12 was injected into mice deficient for the
IFN-IR (IFN-IR-/-) and the response was
compared with that in control mice. As shown in Fig. 2, A–D,
CD44high CD8+ T cells
showed similar increases in BrdU labeling in
IFN-IR-/- and IFN-IR+/+
mice. Therefore, IL-12 induction of T cell turnover was independent of
IFN-I.
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, E and F).
Nevertheless, this was not an absolute requirement, since some
Ly-6Chigh CD8+ T cells were
present in the IFN-IR-/- mice. Injection of
IL-12 resulted in increased numbers of Ly-6Chigh
CD8+ T cells in both control and IFN-
IR-/- mice. The implication is that the
up-regulation of Ly-6C observed in normal mice after IL-12 injection is
partly IFN-I independent.
Role of IFN- in the induction of memory phenotype T cell
turnover
Since IL-12 is a strong inducer of IFN- expression
(26), IL-12 might stimulate CD44high
CD8+ cells via production of IFN-. To examine
this possibility, we compared the response to IL-12 injection in mice
deficient for IFN- with that in control mice. Strikingly,
CD8+ T cells showed little if any increase in
BrdU labeling after IL-12 injection into
IFN--/- mice (Fig. 3, A–D). Also, unlike in
control mice, the percentage of CD8+ T cells
expressing high levels of Ly-6C was not increased after IL-12 injection
(Fig. 3, E and F). Therefore, the ability of
IL-12 to induce both bystander proliferation of memory phenotype
CD8+ T cells and up-regulation of Ly-6C was
highly dependent on IFN-.
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, it would be predicted that other cytokines capable of inducing
IFN- should also be able to stimulate the turnover of
CD44high CD8+ T cells in
vivo. To test this hypothesis, we examined the effect on T cell
turnover of IL-18, another strong inducer of IFN- (27).
In fact, the activity of IL-18 was very similar to that of
IL-12. Thus, although addition of IL-18 to purified
CD8+ T cells failed to cause T cell division in
vitro (Fig. 1F), injection of IL-18 stimulated a strong
increase in the BrdU labeling of memory phenotype
CD8+ T cells in vivo (Fig. 4, A and B). Also
like IL-12, IL-18 had only a small effect on the turnover of
CD44high CD4+ T cells (Fig. 4C) and did not stimulate increased BrdU labeling of naive T
cells. Finally, although small increases in BrdU labeling were
detectable among CD44high
CD8+ T cells after IL-18 injection into
IFN--/- mice, proliferation was markedly
reduced compared with that in control mice (Fig. 4, D and
E). Thus, as for IL-12, induction of bystander
CD8+ T cell proliferation by IL-18 is largely
IFN- dependent.
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promote the turnover of memory phenotype
CD8+ T cells. To test directly the ability of
IFN- to stimulate T cell turnover, rIFN- was injected i.v. into
B6 mice and recipients were given BrdU for 3 days. As shown in Fig. 5, IFN- induced marked proliferation
of CD44high CD8+ T cells
but failed to stimulate CD44high
CD4+ T cells. Like IL-12 and IL-18, injection of
IFN- did not affect the turnover of naive phenotype T cells. Thus,
IFN- may indeed serve as a common mediator linking IL-12 and IL-18
to the stimulation of CD44high
CD8+ T cell turnover. This cytokine pathway
appears to be distinct from one that we previously described in which
IFN-I, through the induction of an effector cytokine (see below),
stimulates the turnover of memory phenotype CD8+
T cells.
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stimulates CD8+ T
cell division directly. In fact, addition of IFN- to purified T
cells in vitro does not induce CD8+ T cells to
proliferate (19). However, a clue to the mechanism of
action of this cytokine may come from the fact that injection of
IFN- results in selective proliferation of
CD122high CD8+ T cells
(Fig. 6, A and B).
Like IL-12 (data not shown), IFN- stimulated an equivalent increase
in BrdU labeling of these cells in C3H/HeJ and C3H/HeOuJ mice,
discounting the possibility of contamination with endotoxin. Similarly,
IL-18 also induced proliferation of CD122high but
not CD122low CD8+ T cells
(Fig. 6, C and D). The significance of this
finding is that CD122high
CD8+ T cells proliferate in direct response to
IL-15, which is inducible by IFN- (19). Thus, turnover
of memory phenotype CD8+ T cells in response to
IL-12 injection may be the end result of a cascade of cytokine
production.
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rather than IFN-I. This pathway operates
following injection of at least three cytokines, IFN-, IL-12, and
IL-18. In the case of IL-12 and IL-18, these cytokines presumably
function by inducing the production of IFN-.
It is notable that, despite their strong stimulatory effects in vivo,
IFN-, IL-12, and IL-18 were all unable to induce proliferation of
purified T cells in vitro. Hence, it is likely that the in vivo
function of these cytokines reflects the subsequent production of an
effector cytokine. For several reasons we suspect that IL-15 is the
effector cytokine. First, both IFN-I and IFN- induce the production
of IL-15 mRNA by macrophages in vitro (19). Second, CD122
(IL-2R), an important component of the receptor for IL-15 (and
IL-2), is expressed at a much higher level on memory phenotype
CD44high CD8+ cells than on
CD44high CD4+ cells
(19, 28). Third, virtually all of the T cells responding
to IFN- and IFN-I in vivo are CD122high.
Fourth, IL-15 induces selective stimulation of memory phenotype
CD8+ cells not only in vivo but also in vitro
(19). Fifth, at least for poly(I:C) injection, stimulation
of memory phenotype CD8+ cells by cytokines in
vivo does not apply to CD122-/- mice (unpublished data of
X. Zhang and J. Sprent). Sixth, preliminary results suggest that
memory-phenotype CD8+ T cells do not proliferate
in response to Poly I:C injection after adoptive transfer to
IL-15-/-mice (A. Gulbranson-Judge and J. Sprent,
unpublished data). Based on these findings, our prediction is that both
the IFN-I-dependent and IFN--dependent pathways of in vivo T cell
proliferation will not operate in IL-15-/- mice
(29). We are currently in the process of testing this
prediction.
The notion that IL-15 is the final effector cytokine for in vivo T cell
proliferation elicited by IFN-I and IFN- is in agreement with recent
studies showing a profound deficiency of memory phenotype T cells in
IL-15R-/- (30) and
IL-15-/- (29) mice. Significantly,
the paucity of memory phenotype T cells in these two lines is largely
restricted to CD8+ cells rather than
CD4+ cells. Similarly, selective disappearance of
memory phenotype CD8+ occurs following repeated
injection of anti-CD122 mAb (28). The implication
therefore is that the survival of memory phenotype
CD8+ cells depends crucially upon continuous
stimulation via background levels of IL-15. A corollary of this notion
is that in vivo exposure to agents that lead to increased synthesis of
IL-15 would augment the proliferation of CD44high
CD8+ cells. Our data on the effects of injecting
mice with IL-15-inducing agents such as IFN-I and IFN- are
consistent with this prediction. It is also notable that
IL-15-transgenic mice show a marked overrepresentation of memory
phenotype CD8+ (but not
CD4+) cells (31).
Finally, it should be pointed out that the background rate of turnover
of CD44high CD8+ T cells in
IFN--/- mice was not reduced compared with
control mice (see Figs. 3 and 5). Furthermore, normal numbers of memory
phenotype CD8+ T cells were found in
IFN--/- mice (data not shown). At face
value, these observations indicate that normal
CD8+ T cell homeostasis is not dramatically
altered in the absence of IFN- under resting conditions. This is not
surprising, given that induction of IL-15 production by other means,
including the IFN-I-dependent pathway, will still occur in these mice.
Here, an important question is whether the turnover of
CD44high CD8+ T cells is
reduced in the combined absence of both IFN- and IFN-I. We are
currently breeding IFN-IR-/- x
IFN--/- mice to assess this possibility.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. David F. Tough, Edward Jenner Institute for Vaccine Research, Compton, Newbury, Berkshire RG20 7NN, U.K.
3 Abbreviations used in this paper: IFN-I, type I IFN; IFN-IR, IFN-I receptor; BrdU, bromodeoxyuridine; LN, lymph node.
Received for publication November 29, 2000. Accepted for publication March 6, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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/ T cells in secondary lymphoid organs. J. Exp. Med. 177:891./ enhances the expression of Ly-6 antigens on T cells in vivo and in vitro. Eur. J. Immunol. 16:735.[Medline]
production by T cells. Nature 378:88.[Medline]
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) and CD44high (•)
CD8+ (A and B) or
CD4+ (C) T cells labeled with BrdU is shown
for T cells isolated from LN (A and C) or
spleen (B). Shown in D is the percentage
of LN CD8+ T cells expressing high levels of Ly-6C. Data
represent the mean ± SD for two mice per point. E
and F, CD8+ T cells were purified from
pooled LN of normal B6 mice by cell sorting and placed in culture for
40 h (E) or 72 h (F) in the
presence of BrdU and the indicated cytokine. Data show percent
BrdU+ cells among CD44high (
) or
CD44low (
) CD8+ T cells.
) mice injected with PBS or IL-12. Data
represent the mean ± SD for two mice injected with PBS and two
mice injected with IL-12.
, C3H/HeJ mice injected with
IFN-