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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
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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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The mechanisms responsible for the persistence of T cell memory are unclear. It appears that memory T cell populations are maintained through the homeostatic replication of a subgroup of memory cells and through the intrinsic ability of some memory cells to survive in the resting state for an extended duration (8, 9). Although earlier studies suggested that continued antigenic stimulation is required for maintaining T cell memory (9, 10, 11, 12), recent evidence indicates that CD4+ and CD8+ memory T cell populations persist in the absence of specific or cross-reactive Ags presented by MHC molecules (13, 14, 15). Therefore, it is possible that Ag-independent factors, such as cytokines, are critical for the survival and proliferation of memory T cells. IL-2 enhances the survival of naive T cells and stimulates the proliferation of primary activated lymphocytes (16, 17). In addition, it has been proposed that IL-2 is required for generating and maintaining memory T cells (18, 19). This hypothesis, however, is challenged by the findings that IL-2 programs T cells for activation-induced apoptosis and that IL-2-/- mice are not immunodeficient but instead display exaggerated T cell immunity (4, 17).
In this study, we tested whether IL-2 is required for generating and maintaining CD8+ memory T cells by analyzing the long-term survival, phenotype, and functional characteristics of Ag-activated IL-2-replete (IL-2+/+) (3) and IL-2 gene-knockout (IL-2-/-) CD8+ TCR-transgenic (TCR-tg)3 lymphocytes (2C) in an adoptive transfer model. The 2C TCR recognizes the Ld MHC class I Ag and can be tagged by a clonotypic Ab (1B2) that permits the detection of small numbers of Ag-specific cells in vivo (20). We demonstrate here that CD8+ memory T cells can be efficiently generated and maintained in the absence of IL-2. However, IL-2 increased the size of the CD8+ memory population if present during T cell activation but reduced its size if present during the maintenance period. These findings indicate that IL-2 has a dual role in the generation and maintenance of CD8+ T cell memory.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c (H-2d), C57BL/6 (H-2b) Rag1-/-, and C57BL/6 IL-2-/- mice were purchased from The Jackson Laboratory (Bar Harbor, ME). C57BL/6 2C TCR-tg mice were provided by Dr. Dennis Loh and bred at the Veterans Affairs Medical Center animal facility (Atlanta, GA) (20). IL-2-deficient 2C mice were generated by cross-breeding C57BL/6 IL-2-/- mice with C57BL/6 2C mice. Genotyping was performed by PCR amplification of DNA extracted from tail clippings. Transgenic and gene-knockout mice were housed under specific pathogen-free conditions.
In vitro generation of effector CD8+ T cells
Splenocytes were isolated from IL-2+/+ and
IL-2-/- 2C mice and stimulated in vitro with
mitomycin C-treated BALB/c splenocytes in RPMI 1640 medium supplemented
with 1 mM L-glutamine, 1% sodium pyruvate, 50 µM 2-ME,
100 U/ml penicillin, 100 µg/ml streptomycin (all from Life
Technologies, Grand Island, NY), and 10% FCS (Sigma, St. Louis, MO). A
total of 50 U/ml recombinant mouse IL-2 (Genzyme, Cambridge, MA) was
added to all cultures. After 96 h of mixed lymphocyte culture,
live cells were isolated by ficoll density centrifugation using
Lympholyte-M (Cedarlane, Hornby, Ontario) and were subsequently
enriched for T cells by nonadherence to nylon wool columns
(Polysciences, Warrington, PA). IL-2+/+ and
IL-2-/- 2C T cell-enriched preparations (a
total of 
2.5 x 107 2C T cells in each)
containing 5 x 106
CD8+1B2+ cells (quantitated
by two-color flow cytometry as described below) were mixed with 3-fold
more (7.5 x 107) naive T cell-enriched
IL-2+/+ and IL-2-/-
non-TCR-tg C57BL/6 splenocytes, respectively, and were then adoptively
transferred by i.v. injection into Rag1-/-
mice. Control Rag1-/- mice were adoptively
transferred with 5 x 106 naive
IL-2+/+ or IL-2-/-
CD8+1B2+ cells mixed with
7.5 x 107 naive T cell-enriched
IL-2+/+ or IL-2-/-
non-TCR-tg C57BL/6 splenocytes, respectively. 2C lymphocytes were mixed
with non-TCR-tg, syngeneic splenocytes before transfer to simulate
physiologic settings in which Ag-specific cells are present at much
lower frequency than in TCR-tg mice. Mice were sacrificed at either 1
wk or 10 wk after adoptive transfer and spleen and lymph node cells
were harvested to test for the presence of
CD8+1B2+ cells. Memory
cells were identified according to the following criteria: 1)
survival advantage over naive cells; 2) high CD44 and low CD62L
expression
(CD44highCD62Llow); and 3)
ability to mount a recall CTL response. Absence of IL-2 production in
Rag1-/- hosts that received
IL-2-/- lymphocytes was confirmed by 35 cycles
of RT-PCR amplification of splenic and lymph node mRNA.
In vivo generation of memory T cells
Naive IL-2+/+ or
IL-2-/- 2C T cell-enriched splenocyte
preparations (a total of 2.5 x 107 2C T
cells in each) that contain 5 x 106
CD8+1B2+ cells were mixed
with 3-fold more (7.5 x 107) naive T
cell-enriched IL-2+/+ or
IL-2-/- non-TCR-tg splenocytes, respectively,
and were subsequently adoptively transferred to
Rag1-/- mice by i.v. injection. Twenty-four
hours later, the Rag1-/- hosts were immunized
i.p. with mitomycin C-treated BALB/c splenocytes (which express the
Ld MHC class I Ag recognized by the 2C TCR).
Control mice were injected with PBS i.p. Ten weeks after immunization,
mice were sacrificed and lymph node cells and spleen cells were
harvested to test for the presence of
CD8+1B2+ cells. Memory
cells were identified according to the same criteria described in the
previous section.
To test the influence of exogenous IL-2 on the generation of CD8+ memory T cells, 5 µg recombinant murine IL-2 (Genzyme, Boston, MA) was administered i.p. to Rag1-/- mice harboring IL-2-/- 2C lymphocytes on days 0 and 2 after immunization with BALB/c splenocytes. Control mice received PBS injections i.p. On day 4, lymph node cells were harvested and adoptively transferred to a second Rag1-/- host. Ten weeks later, CD8+1B2+ cells were quantitated as described in the previous paragraph. To test the influence of IL-2 on the maintenance of CD8+ memory T cells, Rag1-/- mice harboring IL-2-/- 2C lymphocytes were immunized with BALB/c splenocytes in the absence of exogenous IL-2. Four days later, lymph node cells were harvested and adoptively transferred to a second Rag1-/- host which was subsequently injected i.p. with 5 µg recombinant IL-2 twice weekly. Ten weeks later, CD8+1B2+ cells were quantitated as described in the previous paragraph.
Flow cytometry
Adoptively transferred 2C lymphocytes (CD8+1B2+) were identified in Rag1-/- hosts by incubating pooled lymph nodes cells or splenocyte with PE-conjugated rat anti-mouse CD8a (53–6.7; PharMingen, San Diego, CA), mouse IgG1 anti-2C TCR clonotypic Ab (1B2), and FITC-conjugated rat anti-mouse IgG1 (PharMingen) or, in some experiments, biotinylated rat anti-mouse IgG1 followed by streptavidin-PerCP (PharMingen). To detect cell surface markers, the following Abs (all from PharMingen) were used: FITC-conjugated rat anti-mouse CD44 (1 M7) and FITC-conjugated rat anti-mouse CD62L (MEL-14). The appropriate isotype control Abs were used as negative controls (all from PharMingen). Stained cells were washed and analyzed by two- or three-color flow cytometry on a FACScan (Becton Dickinson, Mountain View, CA). The CD44 and CD62L phenotype of naive and memory T cells was determined by gating on CD8+1B2+ cells.
CTL activity
Rag1-/- mice were adoptively transferred with naive or activated IL-2+/+ and IL-2-/- 2C lymphocytes as described above and challenged in the footpads with mitomycin C-treated BALB/c splenocytes 10 wk later. After 3 days, popliteal and inguinal lymph node cells were pooled and immediately analyzed in an ex vivo CTL assay. Allospecific CTL activity was measured by incubating the lymph node cells with either P815 (H-2d) target cells (American Type Culture Collection (ATCC), Manassas, VA) or third party cells LK35.2 (H-2k) (ATCC) for 3 h. 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) (21). Experiments in which spontaneous calcein release was more than 25% of maximal release were excluded. Ag-specific cytotoxic activity was calculated according to the following formula: % specific lysis = 100 x [(sample release - spontaneous release)/(maximum release - spontaneous release)].
5-Bromo-2-deoxyuridine (BrdU) labeling
Naive IL-2+/+ or
IL-2-/- 2C T cell-enriched splenocyte
preparations that contain 5 x 106
CD8+1B2+ cells were mixed
with 7.5 x 107 naive T cell-enriched
IL-2+/+ or IL-2-/-
non-TCR-tg splenocytes, respectively, and were subsequently adoptively
transferred to Rag1-/- mice by i.v. injection.
Twenty-four hours later, the Rag1-/- hosts were
immunized i.p. with mitomycin C-treated BALB/c splenocytes. At 10 wk,
0.8 mg/ml BrdU was added to the drinking water for 7 days, after which
the mice were sacrificed and lymph node cells were harvested. A
separate group of Rag1-/- mice harboring
IL-2-/- 2C memory lymphocytes was injected with
5 µg recombinant murine IL-2 i.p. twice during the BrdU labeling
period. Surface staining of lymph node cells with 1B2 and anti-CD8
was performed as described in the previous sections. Cells were then
fixed in 70% ethanol followed by 1% paraformaldehyde and incubated
with 50 Kunitz/ml of DNAase I (Sigma) for 10 min at room temperature.
The cells were subsequently stained with FITC-conjugated anti-BrdU
Ab (Becton Dickinson) and three-color flow analysis was performed. The
percentage of BrdU+ cells was determined after
gating on the CD8+1B2+
population.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To study the role of IL-2 in the maintenance of Ag-specific CD8+ T cell memory, IL-2+/+ and IL-2-/- 2C lymphocytes were activated in vitro in the presence of excess IL-2 and were then transferred to Rag1-/- hosts. Control Rag1-/- mice were adoptively transferred with naive IL-2+/+ or IL-2-/- 2C lymphocytes. Both activated and naive 2C lymphocytes were mixed with naive, non-TCR-tg, syngeneic T lymphocytes before adoptive transfer to simulate physiologic settings in which Ag-specific T cells are present at much lower frequency than in TCR-tg mice. Because 2C lymphocytes can be identified by a clonotypic Ab (1B2), this experimental model allowed us to compare the in vivo survival, phenotype, and functional characteristics of previously activated CD8+ T cells to that of naive cells in the presence or absence of IL-2. In the experiments that follow, similar findings were obtained whether lymph node or spleen cells were analyzed. Therefore, only the results of lymph node analysis are shown.
One week after adoptive transfer, the number of previously activated
IL-2+/+ or IL-2-/- 2C
(CD8+1B2+) lymphocytes
present in the lymph nodes of Rag1-/- hosts was
similar to that of naive IL-2+/+ or
IL-2-/- 2C lymphocytes (Fig. 1
, A and B). No
significant difference in the number of
CD8+1B2+ cells was observed
between the IL-2+/+ and
IL-2-/- 2C populations (Fig. 1, A
and B). However, at 10 wk after adoptive transfer, the
number of previously activated IL-2+/+ or
IL-2-/- 2C lymphocytes significantly exceeded
that of naive IL-2+/+ or
IL-2-/- 2C lymphocytes (Fig. 1, A
and B), indicating that previously activated lymphocytes
have a survival advantage over their naive counterparts. Like the naive
2C TCR-tg (CD8+1B2+)
population, the naive non-TCR-tg
(CD8+1B2-) population had
diminished dramatically by 10 wk (Fig. 1A). Moreover, at 10
wk after adoptive transfer, previously activated
IL-2-/- 2C lymphocytes were present in
significantly greater numbers than previously activated
IL-2+/+ 2C lymphocytes (Fig. 1, A and
B). These findings suggest that long-lived, Ag-specific,
CD8+ memory T cells are present in
Rag1-/- mice adoptively transferred with
previously activated 2C lymphocytes, and that the number of memory
cells is increased, rather than diminished, in the absence of
IL-2.
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C, previously activated
IL-2+/+ and IL-2-/- 2C
lymphocytes, present at 10 wk after adoptive transfer, express high
levels of CD44 (CD44high) and low levels of CD62L
(CD62Llow), a phenotype associated with
CD8+ memory T cells in mice. We then asked
whether a recall immune response can be elicited in
Rag1-/- mice that received previously activated
2C lymphocytes. As shown in Fig. 1D, Ag-specific stimulation
induced a rapid and strong CTL response in mice that harbored
previously activated IL-2+/+ or
IL-2-/- lymphocytes but not in those that
harbored naive cells. These findings prove that neither the long-term
maintenance nor the recall response of CD8+
memory T cells is dependent on IL-2. IL-2 is not required for in vivo generation of CD8+ memory T cells
To test whether IL-2 is essential for generating
CD8+ T cell memory, we adoptively transferred
naive IL-2+/+ or IL-2-/-
2C lymphocytes to Rag1-/- hosts. As in the
previous model, naive 2C lymphocytes were mixed with naive, non-TCR-tg,
syngeneic T lymphocytes before adoptive transfer. The adoptively
transferred mice were then challenged with either PBS or
Ld-bearing allogeneic splenocytes. Ten weeks
later, lymph node cells were analyzed by flow cytometry. A
significantly larger number of
CD8+1B2+ cells was detected
in allostimulated than in naive mice (Fig. 2). The number of long-lived
CD8+1B2+ cells was
comparable in mice that harbored either IL-2+/+
or IL-2-/- 2C lymphocytes. Moreover, long-lived
CD8+1B2+ cells present in
allostimulated mice, but not those present in naive mice, exhibited a
CD44highCD62Llow phenotype
(data not shown). These findings indicate that
CD8+ memory T cells can be generated in vivo in
the absence of IL-2. Similar findings were obtained when spleen cells
were anlayzed (data not shown).
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We have observed in this study that the size of the
CD8+ T cell memory population is increased if 2C
lymphocytes are activated in vitro in the presence of IL-2 and then
maintained in vivo in its absence (Fig. 1). However, when 2C
lymphocytes were activated and maintained in vivo in the absence of
IL-2, the size of the resulting CD8+ T cell
memory population was similar to that observed if IL-2 was present
(Fig. 2). These findings suggest that IL-2 has divergent effects on the
generation and maintenance of memory T cells. To study the effect of
IL-2 on memory generation, IL-2-/- 2C
lymphocytes were activated in vivo in the presence or absence of
exogenous IL-2 and were then maintained in a second
Rag1-/- host without further IL-2
administration. To study the effect of IL-2 on memory maintenance,
IL-2-/- 2C lymphocytes were activated in vivo
in the absence of exogenous IL-2 and were then maintained in a second
Rag1-/- host that received twice weekly
injections of either PBS or recombinant IL-2. In both experiments, the
number of CD8+1B2+ was
quantitated 10 wk after lymphocyte activation. As shown in Fig. 3A, administering IL-2 to mice
at the time of IL-2-/- 2C lymphocyte activation
resulted in a significantly larger number of long-lived
CD8+1B2+ cells (38%
increase over mice injected with PBS), indicating that IL-2 potentiates
the generation of CD8+ T cell memory. In
contrast, repeated administration of IL-2 to mice harboring previously
activated IL-2-/- 2C lymphocytes resulted in a
significantly smaller number of long-lived
CD8+1B2+ cells (30%
decrease compared with mice injected with PBS) (Fig. 3B),
suggesting that IL-2 interferes with the maintenance of
CD8+ T cell memory. Unlike its effects on memory
T cells, IL-2 administration did not alter the number of naive
CD8+1B2+ T cells (Fig. 3, A and B).
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C, the
percentage of BrdU+ cells was 2-fold higher in
IL-2-/- than IL-2+/+
memory cells. Importantly, administering recombinant IL-2 to mice
harboring IL-2-/- 2C memory lymphocytes reduced
BrdU uptake significantly (Fig. 3C). These data indicate
that IL-2 interferes with memory maintenance by decreasing the
proliferation rate of the CD8+ memory T cell
population. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We employed in this study two adoptive transfer models to investigate CD8+ T cell memory. The first model was designed to examine the role of IL-2 in memory maintenance; therefore, IL-2+/+ or IL-2-/- 2C lymphocytes were activated in vitro in the presence of excess IL-2 and then transferred to Rag1-/- hosts to follow their long-term survival. Rag1-/- mice do not produce IL-2 (confirmed by RT-PCR in our study) because they lack lymphocytes. Therefore, the only potential source of IL-2 in these mice is the adoptively transferred lymphocyte population. The second model was designed to examine the role of IL-2 in memory generation; therefore, naive IL-2+/+ or IL-2-/- 2C lymphocytes were transferred to Rag1-/- hosts, activated in vivo, and their survival followed over an extended period of time. We confirmed in our experiments that long-lived, previously activated 2C lymphocytes are CD8+ memory T cells by demonstrating that they have a significant survival advantage over adoptively transferred naive lymphocytes, are CD44highCD62Llow, and exhibit a rapid CTL response upon antigenic restimulation. The adoptive transfer of TCR-tg lymphocytes to lymphocyte-deficient hosts is an established approach to studying CD4+ and CD8+ T cell memory in vivo (2, 3) as it allows for the quantitation and analysis of Ag-specific T cells in a manner which is not possible in non-TCR-tg systems.
The dual role of IL-2 in the generation and maintenance of
CD8+ T cell memory is consistent with its
divergent effects on naive/primary activated T cells and repeatedly
activated T cells. IL-2 promotes the survival of naive T cells and
enhances their clonal expansion upon primary antigenic stimulation
(22, 23). In contrast, IL-2 promotes the Ag-induced
apoptosis of repeatedly activated T cells and thus contributes to the
clonal contraction of effector lymphocytes (24, 25, 26, 27, 28). Our
finding that IL-2 enhances memory generation if present during initial
T cell activation is consistent with the hypothesis that the size of
the memory pool is directly proportional to the magnitude of T cell
clonal expansion during the primary immune response (1).
However, we identified in this study an inhibitory effect of IL-2 on
the proliferation of CD8+ memory T cells which
leads to a smaller memory pool. Although it is possible that IL-2
decreases BrdU uptake by memory T cells by promoting activation-induced
cell death (AICD), this is an unlikely event because memory T cells are
thought to be resistant to AICD (2). Furthermore, our
finding that IL-2 suppresses rather than stimulates memory T cell
proliferation is consistent with a recent report showing that in vivo
inhibition of IL-2 increases the cycling of memory-phenotype
CD8+ T cells in mice (29).
Therefore, the results suggest that IL-2 could serve as a vaccine
adjuvant if used at the time of primary antigenic stimulation but will
lead to a paradoxical decline in the memory population if used during
the posteffector phase of the immune response. Conversely, when
designing immunosuppresive or tolerance-inducing strategies, one should
take into account the possibility that long-term IL-2 blockade could
amplify the pool of unwanted allospecific memory T cells. It is
important to note, however, that the net effect of endogenous IL-2 on
the size of the CD8+ memory pool in an immunized
animal is negligible (Fig. 2), possibly because the enhancing effect of
IL-2 on memory generation is offset by its inhibitory effect on memory
maintenance.
Our demonstration that IL-2 is not required for the maintenance of CD8+ T cell memory contradicts the results of Ke et al. (18), who observed that the number of CD8+ memory T cells declines significantly in the absence of IL-2. Unlike our study, Ke et al. employed an in vivo model based on the adoptive transfer of an IL-2-dependent CD8+ T cell line. The requirements for survival and proliferation of IL-2-dependent T cell lines differ from those of primary T cells because prolonged in vitro culture with IL-2 may modulate the expression of cytokine receptors and survival genes in T lymphocytes. Saparov et al. (19), in contrast, observed that IL-2 expression during primary T cell activation correlates with the magnitude of the secondary immune response elicited 1 wk after primary activation, leading the authors to suggest that IL-2 promotes effector/memory T cell generation. Our findings extend this observation by demonstrating that IL-2 enhances CD8+ memory T cell generation in an established model of immunologic memory. However, our results identify a paradoxical effect of IL-2, specifically that it interferes with the maintenance of long-lived CD8+ memory T cells.
Cytokines other than IL-2 may be critical for generating and sustaining
T cell memory. Exogenous IL-15 is a potent and selective stimulator of
memory-phenotype CD8+ T cells in vivo (29, 30). Moreover, memory-phenotype CD8+ T
cells are selectively reduced in number in IL-15R
or IL-15
gene-knockout mice (31, 32). Unlike IL-2, IL-15 is
ubiquitously expressed by stromal cells in multiple tissues making it a
likely cytokine to maintain the memory T cell pool in the absence of
ongoing inflammation or immunity (31).
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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, Veterans Affairs Medical Center and Emory University, Research 151N, 1670 Clairmont Road, Atlanta, GA 30033.
3 Abbreviations used in this paper: tg, transgenic; BrdU, 5-bromo-2-deoxyuridine.
Received for publication April 17, 2000. Accepted for publication June 28, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/ß T lymphocytes for apoptosis. Nature 353:858.[Medline]
)-deficient T cells expressing a transgenic antigen receptor. J. Immunol. 158:3738.[Abstract]
chain (c) in regulating IL-2- dependent, activation-induced CD8+ T cell death. J. Immunol. 163:3131.This article has been cited by other articles:
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, p < 0.05 compared with
IL-2+/+ activated cells. C, Flow cytometric
analysis of CD62L and CD44 expression on naive (solid histograms) or
previously activated (open histograms) IL-2+/+ and
IL-2-/- CD8+1B2+ cells present at
10 wk after adoptive transfer. Histograms shown are representative of
four experiments. D, CTL recall response of
Rag1-/- hosts at 10 wk after adoptive transfer. Ex vivo
CTL activity was measured 3 days after challenging
Rag1-/- hosts with BALB/c splenocytes (mean ± SD,
n = 4).
