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The Carlos and Marguerite Mason Transplantation Research Center, Renal Division, Department of Medicine, Emory University and Veterans Affairs Medical Center, Atlanta, GA 30033; and
Pathology and Laboratory Medicine, Veterans Affairs Medical Center and State University of New York, Buffalo, NY 14215
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, ß, and 
. The subunit is specific for the IL-2R,
the ß subunit is shared with the IL-15R, and the subunit is also
a component of the IL-4R, IL-7R, IL-9R, and IL-15R (3, 4). In vitro
studies have shown that IL-2 regulates lymphocyte proliferation,
differentiation, and function (1, 2). IL-2 drives the clonal expansion
of Ag-activated CD4+ T cells and regulates their
differentiation in culture into either IFN-- or IL-4-producing Th
lymphocytes; it also promotes CTL precursor differentiation and
activates NK cells, B lymphocytes, and macrophages.
IL-2 gene-knockout
(IL-2-/-)3 mice
have been used along with IL-2R (IL-2R-/-) and
IL-2Rß (IL-2Rß-/-) gene-knockout mice to investigate
the role of IL-2 in context of the whole immune system (4, 5).
Unexpectedly, mice that do not produce IL-2 (IL-2-/-) or
those that lack functional high-affinity IL-2Rs
(IL-2R-/- and IL-2Rß-/-) were found to
be immunocompetent (6, 7, 8, 9). When exposed to normal bacterial flora,
these mice displayed lymphoid hyperplasia due to an increased
proliferation of mature T and B cells and developed severe autoimmunity
that was characterized by hemolytic anemia or inflammatory bowel
disease (8, 9, 10, 11). These findings suggest that IL-2 plays a dual role in
the immune system. On one hand, it has a redundant mitogenic role that
can be replaced by other lymphocyte growth factors such as IL-4, IL-7,
IL-9, and IL-15. On the other hand, it is critical for limiting immune
responses against foreign or self Ags (12, 13, 14, 15, 16).
The redundant role of IL-2 in alloimmunity is underscored by data showing that IL-2-/- mice acutely reject pancreatic islet allografts and generate an effective CTL response to allogeneic tumor cells (17). It is not known, however, whether IL-2 contributes to the induction of transplantation tolerance or long-term allograft acceptance by limiting alloimmune responses. To test this hypothesis, we compared vascularized cardiac allograft survival in wild-type (wt) (IL-2+/+) mice with that in IL-2-/- mice that had been treated with CTLA4Ig, a recombinant fusion protein that blocks the B7-CD28 T cell costimulatory pathway and induces long-term allograft survival in rodents (18, 19, 20, 21). We report that IL-2 is essential for the induction of long-term allograft survival. We also provide evidence that IL-2 is critical for limiting alloantigen-induced T cell proliferation in vivo, at least in part by promoting the apoptosis of activated T lymphocytes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male C3H/He (H-2k), wt BALB/c (H-2d), and IL-2-/- BALB/c (H-2d) mice were purchased from The Jackson Laboratory (Bar Harbor, ME) (6). All IL-2-/- mice were bred at the Emory University/Veterans Affairs Medical Center animal facility in microisolators that had been supplied with sterile food and water (specific pathogen-free environment). Hematocrits of IL-2-/- mice were checked periodically to ensure the absence of autoimmune hemolytic anemia. The inactivation of IL-2 gene function in these animals was confirmed by performing an IL-2-specific ELISA (Genzyme, Cambridge, MA) on splenocyte supernatants that were collected at 0, 24, 48, 72, and 96 h following Con A stimulation (3 µg/ml).
Reagents used in vivo
Human rCTLA4Ig was provided by Dr. Peter S. Linsley (Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA). Neutralizing rat anti-mouse IL-2 mAb was purchased from Genzyme. Reagents were diluted in endotoxin-free PBS (Life Technologies, New Haven, CT) and sterile-filtered before use.
Transplantation procedures
Fully allogeneic (MHC class I- and class II-disparate), vascularized, heterotopic (intraabdominal) heart transplantation was performed as described previously (22) using 8- to 10-wk-old male C3H/He donors and 6- to 8-wk-old male IL-2+/+ and IL-2-/- BALB/c recipients. Mice received 200 µg of human CTLA4Ig i.p. on the day 2 posttransplantation or were left untreated. A separate group of IL-2+/+ recipients that had been treated with CTLA4Ig also received 250 µg of neutralizing rat anti-mouse IL-2 mAb (Genzyme) i.p. at 2 days before and 4 days after transplantation. Rejection was identified by a loss of palpable cardiac contractions, at which time the recipient was sacrificed and the allograft was removed for analysis. Cardiac allograft survival of >100 days was considered long-term survival. To determine whether CTLA4Ig induced alloantigen-specific unresponsiveness (transplantation tolerance), C3H/HeJ and third-party C57BL/6 (H-2b) (The Jackson Laboratory) full-thickness torso skin was transplanted to IL-2+/+ recipients whose heart allografts were still functioning past the 100-day mark. Skin rejection was defined as >90% necrosis of the allograft. All procedures conformed to International Animal Care and Use Committee standards. A statistical analysis of survival data was performed using the Mann-Whitney U test.
CTL generation
We injected 6- to 8-wk-old male IL-2+/+ and IL-2-/- BALB/c (H-2d) mice i.p. on days 0 and 9 with 1 x 107 C3H/He splenocytes suspended in PBS. Mice were sacrificed on day 13; their splenocytes were enriched for T lymphocytes by applying to nylon wool columns (Polysciences, Warrington, PA) (23) and were assayed immediately for allospecific CTL activity by incubating with either 1 x 105 Con A-activated C3H/He (H-2k) splenocytes or P815 (H-2d) target cells (American Type Culture Collection, Manassas, VA) for 2.5 h (24). Target cells were preloaded with calcein-AM (Molecular Probes, Eugene, OR), and calcein release was measured in a LS50B luminescence spectrometer (Perkin Elmer, Foster City, CA) (25). Experiments in which the spontaneous calcein release was >30% of maximum release were rejected. Allospecific cytotoxic activity was calculated according to the following formula: Percentage of specific lysis = 100 x ([test release - spontaneous release]/[maximum release - spontaneous release]).
Histopathology
Formalin-fixed, paraffin-embedded cardiac allograft tissue that had been removed at the time of rejection was stained with hematoxylin and eosin or periodic acid-Schiff and examined by a pathologist (F.K.B.) who was unaware of the identity of the recipients. Acute cellular rejection was graded according to the criteria of the International Society for Heart Transplantation (26).
Reverse transcription PCR
Cardiac allograft and spleen tissue that had been resected at
time of rejection was snap-frozen in liquid nitrogen. RNA was extracted
in guanidinium salt solution and purified by the CsCl gradient method
(27). A total of 5 µg of total RNA was reverse-transcribed using
oligo(dT) primers and Superscript reverse transcriptase according to
the manufacturer’s instructions (Life Technologies). Next, 10% of
cDNA was subjected to 30 cycles of PCR amplification in a Perkin Elmer
Thermocycler 480 using mouse IL-2-, IFN--, TNF--, and
IL-4-specific primer pairs (28). Fifteen percent of each PCR reaction
was electrophoresed on 2% SeaKem LE agarose gels (American
Bioanalytical, Natick, MA) and stained with ethidium bromide. RT-PCR
controls included "no RNA" (blank) and "no reverse
transcriptase" reactions.
5-bromo-2'-deoxyuridine (BrdU) labeling of T cells
IL-2+/+ and IL-2-/- BALB/c mice were injected in the footpads with 1 x 107 C3H/He splenocytes suspended in PBS. Control mice were injected in the footpads with 1 x 107 syngeneic splenocytes. After 4 days, mice were pulsed i.p. with 0.8 mg of BrdU (Sigma, St. Louis, MO) and sacrificed after 24 h. Popliteal and inguinal lymph node (LN) cells were isolated and enriched for T cells by applying to nylon wool columns (Polysciences). Surface staining for murine CD4 and CD8 was performed using phycoerythrin-conjugated Abs (PharMingen, San Diego, CA). Cells were then fixed in 70% ethanol followed by 1% paraformaldehyde and incubated with 50 Kunitz/ml of DNase I (Sigma) for 10 min at room temperature (29). Cells were subsequently stained with FITC-conjugated anti-BrdU Ab (Becton Dickinson, Mountain View, CA) and analyzed by single- and two-color flow cytometry on a Becton Dickinson FACScan.
Detection of T cell apoptosis
IL-2+/+ and IL-2-/- BALB/c mice were immunized in the footpads with 1 x 107 C3H/He splenocytes on days 0 and 4. Control mice were injected in the footpads with 1 x 107 syngeneic splenocytes. Cells were pooled from the popliteal and inguinal LNs of each mouse on day 6 and enriched for T cells by applying to nylon wool columns (Polysciences). Cells were then fixed in 2% paraformaldehyde, permeabilized with 0.1% Triton X-100 in 0.1% sodium citrate, and labeled with fluorescein-tagged deoxyuridine triphosphate (dUTP) by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) method according to the manufacturer’s instructions (In Situ Cell Death Detection Kit, Boehringer Mannheim, Mannheim, Germany). Cells were then analyzed by single-color flow cytometry on a Becton Dickinson FACScan.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Steiger et al. previously demonstrated that IL-2-/-
mice reject nonvascularized pancreatic islet cell transplants and
generate a specific CTL response to allogeneic tumor cells (17). To
determine whether IL-2 is essential for the acute rejection of
vascularized allografts, we transplanted C3H/He hearts to untreated
IL-2+/+ and IL-2-/- BALB/c recipients. As
shown in Figure 1
A, acute
cardiac allograft rejection was not delayed in the absence of IL-2; the
median survival times (MSTs) of hearts transplanted to untreated
IL-2+/+ and IL-2-/- recipients were 6 and 5
days, respectively. IL-2+/+ and IL-2-/- mice
generated significant allospecific CTL activity when immunized with
allogeneic splenocytes; however, CTL activity was lower in the absence
of IL-2 (Fig. 1B).
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CTLA4Ig administration on day 2 posttransplantation resulted in
long-term cardiac allograft acceptance (>100 days) in 30% of
IL-2+/+ recipients but in none of the IL-2-/-
recipients (Fig. 2). The MST of heart
allografts was significantly longer in the IL-2+/+ group
(38 days; n = 10) than in the IL-2-/-
group (13 days; n = 10) (p =
0.001; Mann-Whitney U test). This finding was confirmed by
the administration of neutralizing IL-2 Abs to IL-2+/+
recipients that had been treated with CTLA4Ig. As shown in Figure 2, in
vivo neutralization of IL-2 around the time of transplantation blocked
long-term allograft survival (MST = 18 days; n =
6) (p = 0.02 when compared with the
IL-2+/+ group; Mann-Whitney U test). C3H/He skin
transplants were acutely rejected by CTLA4Ig-treated
IL-2+/+ recipients that had accepted primary heart
allografts, suggesting that donor-specific tolerance was not achieved
in this model. Cardiac grafts, however, continued to function despite
the rejection of skin grafts, suggesting that the response to skin was
directed against skin-specific minor histocompatibility Ags (30).
Syngeneic hearts that had been transplanted to IL-2-/-
recipients survived indefinitely (Fig. 2), indicating that
alloantigen-independent factors did not contribute to early allograft
loss in the IL-2-/- group. Moreover, hemolytic anemia was
not observed in IL-2-/- recipients. The hematocrit
(mean ± SD) of IL-2-/- recipients at the time of
allograft rejection (44% ± 4; n = 7) was comparable
with that of IL-2+/+ recipients (43% ± 2;
n = 4).
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Cardiac transplants were analyzed at the time of heart beat cessation. Allograft pathology in either untreated or CTLA4Ig-treated IL-2-/- mice was characterized by a diffuse and extensive cellular infiltrate consisting of lymphocytes, monocytes, neutrophils, and occasional eosinophils. There was also evidence of vasculitis, myocyte necrosis, interstitial edema, and hemorrhage. These findings were consistent with grade 3 to 4 acute cellular rejection, which was also observed in cardiac allografts that were rejected by untreated IL-2+/+ recipients. Long-term-accepted cardiac allografts removed from CTLA4Ig-treated IL-2+/+ mice revealed interstitial fibrosis and focal mononuclear cell infiltrates that occasionally involved vessel walls. The histopathology of the cardiac allografts rejected by CTLA4Ig-treated IL-2+/+ recipients was similar to that observed in the allografts rejected by untreated mice. An examination of functioning, syngeneic heart grafts that had been removed from IL-2-/- mice at 100 days posttransplantation showed normal myocardial architecture and rare lymphocytes.
Intragraft cytokine mRNA expression
Heart allografts that had been removed from IL-2+/+
and IL-2-/- mice at the time of rejection were analyzed
for cytokine expression by nonquantitative RT-PCR. IL-2 mRNA was not
detected in allografts that were rejected by either untreated or
CTLA4Ig-treated IL-2-/- recipients. In contrast, the
expression of other T cell-derived cytokines such as IFN-, TNF-,
and IL-4 was comparable with that seen in grafts rejected by
IL-2+/+ mice. IL-2 mRNA was not detected in spleen tissue
removed from IL-2-/- recipients. The latter finding
confirms the absence of IL-2 expression by donor passenger leukocytes
that could have migrated to the spleens of recipients.
Increased alloantigen-induced LN T cell proliferation in IL-2-/- mice
IL-2-/- mice display excessive lymphoid hyperplasia
upon colonization with normal bacterial flora (10). Therefore, we
investigated whether alloantigen exposure also leads to unregulated T
lymphocyte proliferation in these mice. In vivo allogeneic stimulation
resulted in a significantly greater percentage of BrdU+ T
lymphocyte-enriched LN cells in IL-2-/- mice compared
with IL-2+/+ mice (Fig. 3).
An exaggerated proliferation of IL-2-/- T cells was
detected in both the CD4+ and CD8+
subpopulations (data not shown). CTLA4Ig, which was administered 2 days
after allogeneic stimulation, inhibited BrdU uptake by
IL-2+/+ T lymphocytes to the level seen in mice primed with
syngeneic cells (Fig. 3). In contrast, CTLA4Ig inhibited
IL-2-/- T lymphocyte proliferation only partially (Fig. 3). These data indicate that alloantigenic stimulation in the absence
of IL-2 leads to deregulated in vivo T cell proliferation.
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To investigate the role of IL-2 in regulating the survival of
activated T lymphocytes, we compared T cell apoptosis between
IL-2+/+ and IL-2-/- mice following repeated,
in vivo stimulation with allogeneic spleen cells. The population of
TUNEL+ cells observed in the T lymphocyte-enriched LNs of
allostimulated IL-2+/+ mice was significantly greater than
that observed in allostimulated IL-2-/- mice (Fig. 4). CTLA4Ig treatment increased the
relative number of TUNEL+ cells from 9 to 14% of gated
cells in allostimulated IL-2+/+ mice
(p < 0.05, ANOVA) and from 2 to 4% of gated
cells in allostimulated IL-2-/- mice
(p < 0.05, ANOVA) (Fig. 4). CTLA4Ig did not
increase apoptotic T cells in the LNs of IL-2+/+ or
IL-2-/- control mice that had been stimulated with
syngeneic spleen cells. These findings indicate that CTLA4Ig enhances
the apoptosis of activated but not resting T lymphocytes, and that
IL-2-independent pathways also play a role in CTLA4Ig-induced
apoptosis.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Severe autoimmune hemolytic anemia has been described in IL-2-/- and IL-2R-/- BALB/c mice exposed to normal bacterial flora (8, 9, 10). Therefore, it can be argued that the early loss of cardiac allografts in CTLA4Ig-treated IL-2-/- mice resulted from alloantigen-independent factors such as generalized autoimmunity. We do not believe that this was the case in our experiments because: 1) IL-2-/- mice were kept in a specific pathogen-free environment and did not develop autoimmune manifestations, 2) the syngeneic heart grafts transplanted to IL-2-/- recipients survived indefinitely and did not exhibit significant lymphocytic infiltrates, and 3) the histopathology of the cardiac allografts removed from IL-2-/- mice was consistent with acute cellular rejection. We also demonstrated that the administration of IL-2-neutralizing Ab to wt recipients at the time of transplantation prevented the induction of long-term allograft survival. This observation strongly suggests that the failure to achieve allograft acceptance in IL-2-/- mice is due to IL-2 deficiency in the adult animal rather than to altered cytokine networks that could have developed in the gene-knockout embryo.
We also observed in this study that in vivo allostimulation in the
absence of IL-2 leads to exaggerated LN T cell proliferation and
impaired apoptosis of activated T cells. An unregulated expansion of LN
T lymphocytes paralleled the extensive cellular infiltrates that were
observed in the allografts rejected by IL-2-/- mice.
These findings are consistent with previous studies (4, 5). Sadlack et
al. observed that IL-2-/- mice that are exposed to normal
bacterial flora develop lymphadenopathy, splenomegaly, and severe
autoimmunity (10, 11). Enlarged lymphoid organs were characterized by
high numbers of activated T and B lymphocytes. Similarly, excessive
numbers of activated lymphocytes were found in
IL-2R-/- and IL-2Rß-/- mice (8, 9).
Lenardo and coworkers demonstrated that IL-2 predisposes mature T
lymphocytes to apoptosis following repeated stimulation with nominal Ag
in vitro or in vivo (12, 13, 14). Others have confirmed these findings by
demonstrating that superantigen-induced T cell deletion and
Fas-mediated, activation-induced T cell death are impaired in
IL-2-/- and IL-2R-/- mice (8, 15, 16).
In our study, the exaggerated proliferation of IL-2-/- LN
T cells can be partially explained by the reduced apoptosis of these
cells. It is possible that IL-2 limits the proliferation of
alloreactive T lymphocytes by triggering additional feedback
mechanisms. For example, T cell activation up-regulates CTLA4
expression on the cell membrane (31). Subsequently, high-affinity
B7-CTLA4 interactions inhibit cell cycle progression (32, 33). Perez et
al. demonstrated that CTLA4 engagement is crucial for the peripheral
tolerance that is induced by blocking the CD28 T cell costimulation
pathway (34).
TCR ligation in the absence of costimulation has been shown to induce T cell anergy in vitro (35). The anergic state is characterized by absent IL-2 production and, in some cases, is reversed by exogenous IL-2 (35). In contrast, we found that the long-term allograft survival induced by a B7-CD28 blockade in vivo depends upon endogenously produced IL-2. This paradox could have resulted from inherent differences between in vivo and in vitro studies. First, a B7-CD28 blockade does not abolish IL-2 production in vivo; however, it does lead to long-term allograft acceptance (30, 36). Second, in addition to T cell anergy, the deletion of alloantigen-specific T cells may constitute another mechanism by which the B7-CD28 blockade induces long-term allograft survival (37). In fact, we observed in this study that CTLA4Ig increases alloantigen-driven T lymphocyte apoptosis. These findings suggest that activation-induced cell death, which is Fas-mediated (38), may contribute to long-term allograft survival. However, we found that CTLA4Ig administration leads to long-term allograft acceptance in gld mice that lack functional Fas ligand molecules (our unpublished observations). Although these data indicate that the actions of CTLA4Ig are not Fas-mediated, they do not rule out the participation of Fas-independent T cell apoptosis pathways in the induction of long-term allograft survival.
Larsen et al. proposed that the silencing of donor-specific T
lymphocytes in mice treated with inhibitors of B7-CD28 and CD40-CD40
ligand interactions is an active process requiring signaling through
the TCR, because concomitant cyclosporin A administration resulted in a
premature rejection of skin grafts (36). Cyclosporin A suppresses the
synthesis of cytokines such as IL-2 and IFN-, which are secreted by
activated T cells (39). In a previous study, we found that IFN- is
critical for the long-term allograft survival that is induced by
blocking the CD28 and CD40 ligand costimulation pathways (40). In this
study, we demonstrated that IL-2 is also critical for achieving
long-term allograft survival, which further suggests that tolerance
induction is an active process involving T lymphocyte stimulation by
alloantigen. These observations are pertinent to testing CTLA4Ig in
clinical transplantation, in which the majority of patients are treated
with cyclosporin A.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Fadi G. Lakkis, VAMC and Emory University, Research 151N, 1670 Clairmont Road, Atlanta, GA 30033. E-mail address:
3 Abbreviations used in this paper: IL-2-/-, IL-2 gene-knockout strain; IL-2+/+, wild-type strain; BrdU, 5-bromo-2'-deoxyuridine; LN, lymph node; wt, wild-type; MST, median survival time; dUTP, deoxyuridine triphosphate; TUNEL, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling.
Received for publication January 28, 1998. Accepted for publication April 13, 1998.
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is critical for long-term allograft survival induced by blocking the CD28 and CD40L T cell costimulation pathways. J. Immunol. 160:2059.This article has been cited by other articles:
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R. M. Gorczynski, Z. Chen, D. A. Clark, J. Hu, G. Yu, X. Li, W. Tsang, and S. Hadidi Regulation of Gene Expression of Murine MD-1 Regulates Subsequent T Cell Activation and Cytokine Production J. Immunol., August 15, 2000; 165(4): 1925 - 1932. [Abstract] [Full Text] [PDF]
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Z. Dai, A. Arakelov, M. Wagener, B. T. Konieczny, and F. G. Lakkis The Role of the Common Cytokine Receptor {gamma}-Chain in Regulating IL-2-Dependent, Activation-Induced CD8+ T Cell Death J. Immunol., September 15, 1999; 163(6): 3131 - 3137. [Abstract] [Full Text] [PDF]
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X. C. Li, Y. Li, I. Dodge, A. D. Wells, X. X. Zheng, L. A. Turka, and T. B. Strom Induction of Allograft Tolerance in the Absence of Fas-Mediated Apoptosis J. Immunol., September 1, 1999; 163(5): 2500 - 2507. [Abstract] [Full Text] [PDF]
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A. Bushell, M. Niimi, P. J. Morris, and K. J. Wood Evidence for Immune Regulation in the Induction of Transplantation Tolerance: A Conditional but Limited Role for IL-4 J. Immunol., February 1, 1999; 162(3): 1359 - 1366. [Abstract] [Full Text] [PDF]
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BALB/c, H-2d) in untreated
IL-2+/+ (•, n = 6) and
IL-2-/- (
, n = 4) mice. Rejection
was defined as the cessation of palpable heart contractions and was
confirmed histologically. B, Allospecific CTL activity
of BALB/c IL-2+/+ (•) and IL-2-/- (
,
n = 6). Rejection was defined as the cessation of
palpable heart contractions and was confirmed histologically. Syngeneic
hearts that were transplanted to untreated IL-2-/- mice
(
, n = 2) survived indefinitely (>100
days).
