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PLENARY PAPER
From the Molecular Oncology Section, Pediatric Branch,
National Cancer Institute, National Institutes of Heath,
Bethesda, Maryland; Intramural Research Support Program, SAIC
Frederick, National Cancer Institute-Frederick, Frederick, Maryland;
and Experimental Immunology Branch, National Cancer Institute, National
Institutes of Health, Bethesda, Maryland.
Thymic-deficient hosts rely primarily on antigen-driven expansion
to restore the peripheral T-cell compartment following T-cell depletion
(TCD). The degree to which this thymic-independent pathway can restore
immune competence remains poorly understood but has important
implications for a number of clinical conditions including stem cell
transplantation and human immunodeficiency virus (HIV) infection. A
model of HY-mediated skin graft rejection by athymic, TCD mice was used
to show that restoration of naive and recall responses via peripheral
expansion requires transfer of only 25 × 106 lymph node
(LN) cells representing approximately 10% of the T-cell repertoire.
Consitutive expression of bcl-2 in the expanding inocula restored
recall responses to HY at a substantially lower LN cell dose
(1 × 106), which is normally insufficient to induce
HY-mediated graft rejection in athymic hosts. Interestingly, bcl-2 had
no effect on primary responses. Interleukin-7 (IL-7) potently enhanced
thymic-independent peripheral expansion and led to HY graft rejection
using an LN cell dose of 1 × 106 in both primary and
recall models. The restoration of immune competence by IL-7 appeared to
be mediated through a combination of programmed cell death inhibition,
improved costimulation, and modulation of antigen-presenting cell (APC)
function. These results show that immune competence for even stringent
antigens such as HY can be restored in the absence of thymic function
and identify IL-7 as a potent modulator of thymic-independent T-cell regeneration.
(Blood. 2001;97:1525-1533) Acute depletion of the T-cell compartment occurs in
a number of clinical situations including stem cell transplantation,
human immunodeficiency virus (HIV) infection, and after intensive
cytotoxic therapy for cancer. Restoration of immune competence
following T-cell depletion (TCD) requires the regeneration of a
functionally intact, diverse T-cell pool that is capable of responding
to foreign antigens and, potentially, altered self-antigens expressed
by tumors. Previous studies have shown that there are 2 main pathways capable of substantial peripheral T-cell regeneration: thymic-dependent regeneration from bone marrow progenitors and thymic-independent peripheral expansion of mature T-cell populations.1 The
relative contribution of these 2 pathways is dynamic and dependent on
the degree of thymic function. Current concepts hold that the capacity of the host to restore immune competence depends primarily on the
extent to which thymic pathways contribute to T-cell regeneration. However, due to disease, therapy-related toxicity, and age-related changes, thymic function is frequently limiting, resulting in a
relative reliance on thymic-independent peripheral expansion in many
clinical situations associated with TCD.2-8 The degree to
which the peripheral expansion of mature T-cell populations can restore
host immune competence following TCD remains poorly understood and is
the focus of this report.
Peripheral expansion is predicted to give rise to limited immune
competence for a variety of reasons. First, although dramatic expansions in cell number can occur,9-12 hosts
reconstituted in this manner display chronically reduced T-cell
numbers.10,13 Second, because the expansion of peripheral
T cells via this process proceeds from limited numbers of cells and is
heavily influenced by interactions with cognate antigen,14
the regenerated repertoire is susceptible to dramatic
skewing15 and shows limited T-cell receptor
diversity.16-19 Third, the process of peripheral expansion leads to an accumulation of T cells that display a highly activated phenotype.13,20 Continuous or repeated exposure of these
activated T cells to antigens that contribute to the process of
expansion could also provide a signal for programmed cell
death.21,22 This is suggested by studies in patients with
TCD due to HIV infection showing increased susceptibility of T cells to
apoptosis with restimulation in vitro23-27 and by direct
labeling studies in vivo.28-30 Although these observations
could potentially relate to direct or indirect effects of HIV, similar
results have been observed in T-cell-depleted hosts after intensive
chemotherapeutic regimens20 and after stem cell
transplantation,31 suggesting that increased susceptibility to cell death is a common phenomenon in regenerating T-cell populations. Thus, a propensity for programmed cell death in
peripherally expanding T-cell populations may also limit the capacity
of peripheral expansion to restore host immune competence.
Interleukin-7 (IL-7) exerts potent effects on T- and B-cell progenitors
and is absolutely required for early T-cell
development.32-34 Because T-cell development can be
largely restored in IL-7 knockout mice by the concurrent expression of
a bcl-2 transgene,35,36 current models suggest that IL-7
acts primarily by inhibiting programmed cell death of immature
thymocytes during development. Indeed, the administration of IL-7 after
cyclophosphamide or bone marrow transplantation in mice leads to
enhanced T-cell reconstitution, presumably via enhanced
thymopoiesis.37-41
Recent studies have shown that IL-7 is also capable of rescuing mature
T cells from apoptosis induced by glucocorticoids, cytokine withdrawal,
and radiation.42-47 These effects are correlated with
alterations in intracellular levels of bcl-2, bcl-xL, and caspase 3 activity, suggesting modulation of intracellular pathways of
programmed cell death. In this report, we sought to examine the
capacity of peripheral expansion to restore immune competence following
TCD and to investigate the role of programmed cell death in limiting
immune competence following reconstitution by peripheral expansion. Our
results show that programmed cell death plays an important role in
limiting immune competence in thymic-deficient hosts undergoing T-cell
regeneration and, in addition, we have identified IL-7 as a cytokine
that dramatically enhances immune competence in thymic-deficient hosts
reconstituted via this pathway.
Mice and thymectomies
TCD and skin grafting
Cell injections Axillary and inguinal LNs were harvested from syngeneic female mice and placed in iced complete media (RPMI, with 10% heat-inactivated fetal bovine serum, penicillin, streptomycin, L-glutamine, Hepes buffer, nonessential amino acids, sodium pyruvate (all from Gibco Life Technologies, Gaithersburg, MD), and -mercaptoethanol (Sigma, St. Louis, MO). LNs were teased apart with
fine forceps, gently minced with the plunger of a syringe, and passed
through a nylon mesh. The cells were washed twice in iced complete
media, viable cell number was determined with trypan blue
exclusion, and cells were resuspended at the appropriate concentration
for injection via tail vein in RPMI without fetal calf serum at the
doses described.
Male dendritic cells were purified from splenocytes following plate adherence and incubation with IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF). Briefly, male spleens were minced with the plunger of a syringe in iced complete media and passed through a nylon mesh. Red blood cells (RBCs) were lysed with ammonium hydroxide lysing buffer, washed twice in complete media, resuspended in iced Dulbecco phosphate-buffered saline (DPBS; Gibco Life Technologies) and separated over a 50% Percoll gradient by centrifugation at 1800g for 12 minutes. The cell layer was removed, washed twice in complete media, resuspended, and counted using trypan blue exclusion. Viable cells (100 × 106) were loaded onto a 150 × 25-mm tissue culture dish (Falcon 3025, Becton Dickinson, Lincoln Park, NJ), incubated at room temperature for 20 minutes followed by incubation at 37°C/5% CO2 for 2 hours. Nonadherent cells were removed by washing with 50 mL warm complete media, the media was replaced with complete media containing 1 ng/mL GM-CSF and 0.1 µg/mL IL-4 (Peprotech, Rocky Hill, NJ), and the plate was incubated overnight at 37°C/5% CO2. On day 2, the nonadherent fraction was removed by gentle pipetting, washed twice in complete media, resuspended, and counted. A fraction of the cell suspension was analyzed with flow cytometry and the remainder was injected in RPMI intraperitoneally at a dose of 1 × 105 cells per mouse. In vitro studies Single-cell suspensions of RBC-depleted splenocytes were made as described followed by passage over a negative selection T-cell enrichment column (R&D Systems, Minneapolis, MN) according to the manufacturer's instructions. The enriched fraction was washed, counted, and resuspended in complete media. The 24-well plates were coated for 18 hours with 0.1 µg/mL rat antimouse CD3 (clone 145-2C11) in DPBS or with DPBS alone. This concentration of 2C11 is insufficient to induce maximal T-cell proliferation (data not shown). T-cell-enriched splenocytes were plated at 4 × 106 cells/well in 2 mL complete media. Recombinant human IL-7 (Peprotech) was added at a concentration of 10 ng/mL. At the time points indicated, wells were washed, pooled, and analyzed with flow cytometry. For proliferation studies, T-cell-enriched splenocytes were labeled with CFSE (5-[and 6]-carboxyfluorescein diacetate succinimidyl ester; Molecular Probes, Eugene, OR) according to the manufacturer's instructions. Labeled cells were incubated on a 96-well plate coated with anti-CD3 as described above.Flow cytometric analysis Cell suspensions were prepared in staining buffer (Hanks balanced salt solution without phenol red with 0.2% human serum albumin [Sigma] and 0.1% sodium azide [Sigma]). For intracellular labeling, cell suspensions were washed in staining buffer containing 0.03% saponin (Sigma). Prior to antibody labeling, FC III/II
receptors were blocked with monoclonal antibody (clone 2.4G2). The
monoclonal antibodies used were CD4 phycoerythrin (PE) (clone CT-CD4)
and CD8a PE (clone CT-CD8a) (Caltag Laboratories, Burlingame, CA), TCR
chain PE (clone H57-597), CD45R/B220PE (clone RA3-6B2), CD11b PE
(clone M1/70), CD11c FITC (clone HL3), CD45.1/Ly5.2 FITC (clone A20),
CD45.2/Ly5.1 FITC (clone 104), CD54/ICAM-1 FITC (clone 3E2), CD80/B7-1
FITC (clone 1G10), CD86/B7-2 FITC (clone GL-1), CD90.1/Thy 1.1 FITC
(clone HIS51), and CD90.2/Thy1.2 FITC (clone OX-7) (Pharmingen).
Intracellular murine bcl-2 was detected with purified hamster antimouse
bcl-2 (clone 3F11; Pharmingen) and detected with goat antihamster IgG
FITC (Southern Biotechnology Associates). Appropriate isotype controls
were used for all experiments. Annexin V labeling was performed in
phosphate-buffered saline (PBS) containing 10 mM NaOH, 140 mM NaCl, and
2.5 mM CaCl2. Cells were then analyzed in buffer containing
2 µg/mL propidium iodide (Sigma).
Flow cytometric analysis was performed on a single laser FACScan or dual laser FACSCalibur (Becton Dickinson). Fluorescence data were collected and analyzed using CELLQuest software. Viable lymphocyte populations were gated based on forward-scatter and side-scatter characteristics. Statistical analysis Survival analysis was performed on the HY skin graft rejection experiments considering the time of complete rejection in days as the end-point. A dichotomous variable of 1 was assigned if a rejection occurred during the period of observation (100 days) and value of 0 was assigned if rejection did not occur and the event was censored. For each comparison, a log-rank test was performed and the 2-sided P value is reported.
Restoration of immune competence in athymic hosts reconstituted via peripheral expansion is critically dependent on the size of the expanding inocula To assess the capability of hosts reconstituted via peripheral expansion to respond to recall antigen, thymectomized, T-cell-depleted C57BL/6 females were grafted with male tail skin and injected intravenously with 1 × 106 primed LN cells as a source of mature T cells. In the recall model, primed cells refer to LN cells taken from syngeneic female mice within 3 weeks after complete male skin graft rejection. Thymus-bearing mice reject HY-disparate skin grafts within 8 weeks. In contrast, thymectomized, T-cell-depleted mice were unable to reject HY-disparate skin grafts despite administration of primed LN cells as a source for peripheral expansion. Importantly, these mice are capable of rejecting allogeneic skin grafts within 8 to 10 days (data not shown). Therefore, the impairment in T-cell immune competence following reconstitution via thymic-independent pathways is limited to responses to antigen with a low precursor frequency suggesting that a simple limitation in the number of cells bearing antigen-specific T-cell receptor specificities may play a central role.To determine the degree to which the deficiency in HY graft rejection
observed following thymic-independent T-cell regeneration was related
to an inadequate starting T-cell inocula, and, if so, to establish the
size of the inocula required to restore responses to recall antigen,
thymectomized T-cell-depleted mice were reconstituted using
progressively larger primed mature LN inocula. As the dose of primed LN
cells was increased, there is an increase in the rate of graft
rejection (Figure 1A). Indeed,
T-cell-depleted mice reconstituted from 25 × 106 primed
LN cells were able to reject HY grafts at a rate analogous to that
observed in control groups.
To examine the induction of primary immune responses after thymic-independent regeneration, thymectomized T-cell-depleted mice were injected with LN cells from syngeneic female mice naive to male antigen at the same time as enriched male dendritic cells as a sensitizing population. In this model sensitization must occur following transfer into T-cell-depleted hosts. In T-cell-replete mice, sensitization with enriched male dendritic cells accelerated the rate of graft rejection by approximately 2 weeks, confirming the ability of these cells to sensitize to HY antigen (Figure 1B). In contrast, as seen in the recall experiments, thymectomized T-cell-depleted mice reconstituted with 1 × 106 naive LN cells failed to reject male grafts despite sensitization with enriched male dendritic cells. Importantly, titration of the lymph node dose to 25 × 106 LN cells led to complete restoration of responses to HY antigen. Therefore, in both the primary response and the recall model, limitations in the capacity of athymic hosts to respond to nominal antigen could be overcome by supplying increased numbers of T cells for peripheral expansion. These results confirm that the impairment in T-cell responses observed in thymic-deficient hosts is not absolute and can be induced in this setting if sufficient T-cell numbers are provided. Inhibition of apoptosis during reconstitution from a limited T-cell inocula restores responses to recall antigen but not to naive antigen To study the mechanisms that contribute to the limitation in T-cell responses following immune reconstitution via peripheral expansion, subsequent experiments attempted to identify factors limiting peripheral expansion in hosts reconstituted from suboptimal numbers of T cells. Based on observations made in clinical settings associated with TCD,20,31 we hypothesized that increased apoptosis of peripherally expanding T cells could limit immune competence in this setting. To determine whether expanding populations are susceptible to programmed cell death in our model, T cells from thymectomized, T-cell-depleted C57BL/6 (Thy-1.2) mice reconstituted from 10 × 106 congenic B6 PL Thy-1a(Thy-1.1) LN cells were analyzed for apoptosis at various time points after transfer. When analyzed on the day of collection there was no evidence for increased T-cell apoptosis in peripherally expanding cells when compared to normal, nonexpanding populations. However, as shown in Figure 2, peripherally expanding congenic T cells from thymectomized, T-cell-depleted animals collected on day 15 after transfer and restimulated with concanavalin A for 18 hours show increased annexin V staining when compared to nonexpanding controls. This provides evidence that T cells undergoing peripheral expansion in thymectomized T-cell-depleted hosts are susceptible to apoptotic cell death on restimulation and suggested that a loss of T cells to apoptosis during peripheral expansion from an insufficient inocula could potentially play a role in limiting T-cell responses in these hosts.
Although the finding of increased annexin V staining of
restimulated, peripherally expanding T cells, along with the findings of other investigators,20,31 suggests that these cells are prone to apoptosis, it is unclear whether this process contributes to
the limitation in immune responses observed in hosts reconstituted in
this manner. If the loss of peripherally expanding T cells to apoptosis
in our skin graft rejection model contributes to the inability to
induce responses to HY antigen in animals reconstituted from a
suboptimal T-cell number, we hypothesized that inhibition of apoptosis
in vivo could restore HY-mediated graft rejection. Thymectomized
T-cell-depleted mice were injected with 1 × 106 primed
LN cells from female mice expressing an hbcl-2 transgene in
lymphocytes. T cells from these animals are resistant to apoptotic cell
death induced by a number of mechanisms including radiation and
cytokine withdrawal.50,51 As shown in Figure
3A, mice reconstituted via peripheral
expansion of 1 × 106 primed, hbcl-2 transgenic LN cells
were able to rapidly reject HY-disparate skin grafts, whereas mice
reconstituted from the same size inocula of LN cells from nontransgenic
littermate controls were unable to reject these grafts by 100 days.
Therefore, inhibition of apoptosis via constitutive bcl-2 expression
during peripheral expansion is sufficient to restore recall responses
to nominal antigen, thereby confirming the role of apoptosis in
limiting immune responses in this setting. Interestingly, no
significant increase in the rate of graft rejection was observed in
T-cell-replete hosts suggesting that programmed cell death is uniquely
limiting in the setting of TCD.
Given the similar results obtained in the LN cell titration experiments between recall and primary responses detailed above, we predicted that the constitutive expression of bcl-2 transgene in peripherally expanding T cells would also lead to restoration of primary immune responses to HY. Surprisingly, however, 1 × 106 naive hbcl-2 transgenic LN cells sensitized with enriched male dendritic cells failed to restore responses to HY antigen in athymic, T-cell-depleted hosts (Figure 3B). Indeed, the same size inocula of both transgenic and nontransgenic LN cells (25 × 106) was required to fully restore HY responses in this model. These results indicate that, unlike responses to recall antigen, constitutive bcl-2 expression in T cells undergoing thymic-independent regeneration from a limited inocula is insufficient to induce primary responses to HY antigens in thymic-deficient hosts and suggests that additional factors beyond the susceptibility to programmed cell death contribute to limitations in induction of primary T-cell responses in thymic-deficient hosts. IL-7 has diverse effects on mature T cells in vitro, and in vivo administration leads to enhanced peripheral expansion The T cells undergoing peripheral expansion display an activated phenotype regardless of activation status prior to injection into T-cell-depleted hosts.15 Therefore, modulation of T-cell activation could potentially enhance the process of peripheral expansion. To examine the effects of IL-7 on the activation of mature T cells in vitro, T-cell-enriched splenocytes were stimulated with plate-bound anti-CD3 antibody at a suboptimal concentration with and without recombinant human IL-7 (rhIL-7). By day 5, T cells incubated with rhIL-7 plus anti-CD3 displayed increased bcl-2 protein (Figure 4A) consistent with the antiapoptotic effect of this cytokine. In addition, prelabeling of T cells with CFSE indicated that rhIL-7 enhanced proliferation (Figure 4B). By day 7, the number of viable T cells recovered after incubation with rhIL-7 plus anti-CD3 was significantly increased when compared to unstimulated groups or to groups incubated with anti-CD3 alone (Figure 4C). Consistent with prior reports,42-46 these results indicate that IL-7 can have multiple effects on mature T cells including an antiapoptotic effect and a costimulatory effect and, therefore, may be particularly capable of modulating peripheral expansion in vivo.
To test this hypothesis, rhIL-7 was administered at a dose of 5 µg/d intraperitoneally for 28 days to thymectomized, T-cell-depleted C57Bl/6 Ly5.2 mice during peripheral expansion of 10 × 106 Ly5.1+ LN cells. In addition, in the same experiment, the potential for peripheral expansion of hbcl-2 transgenic (Ly 5.1) inocula was determined. As seen in Figure 4D, in vivo administration of rhIL-7 led to a significant increase in Ly5.1+ T-cell number. A similar result was observed in mice receiving hbcl-2 transgenic inocula, further confirming the role for apoptosis in limiting peripheral expansion. Therefore, both rhIL-7 treatment and constitutive expression of bcl-2 numerically enhance the peripheral expansion of mature T cells in athymic T-cell-depleted hosts. IL-7 treatment restores recall and primary immune responses in athymic, T-cell-depleted hosts undergoing immune reconstitution from a limited T-cell inocula Due to the in vitro effects of IL-7 and the potent enhancement of peripheral expansion observed in vivo, we tested whether IL-7 could restore recall responses during reconstitution from suboptimal inocula. As shown in Figure 5A, administration of rhIL-7 during peripheral expansion from a limited primed LN inocula (1 × 106) leads to rapid rejection of HY-disparate skin grafts. Importantly, rejection of male skin grafts in all animals required administration of rhIL-7 along with a primed LN inocula, providing evidence that the effect of IL-7 in this model was dependent on the presence of a population of mature T cells undergoing peripheral expansion. We also tested whether the ability of IL-7 to restore immune responses extended to primary responses. As with recall responses, administration of rhIL-7 also led to rapid rejection of HY-disparate skin grafts in mice reconstituted from a limited naive LN inocula and sensitized with enriched male dendritic cells (Figure 5B). The rhIL-7 appeared to have no effect on responses in T-cell-replete hosts in both recall and primary models. Therefore, IL-7 potently restores immune competence in thymic-deficient hosts undergoing T-cell reconstitution via peripheral expansion from a limited inocula. These findings contrast with the experiments using T-cell inocula constitutively expressing the bcl-2 transgene where effects were only seen with recall responses. Thus, we postulated that the ability of IL-7 to restore immune competence in this setting involves other effects on peripherally expanding T cells beyond a modulation of programmed cell death via up-regulation of bcl-2. In addition, we could not exclude the possibility that IL-7 may also enhance other cell populations critical to the generation of immune responses.
Sensitization with IL-7R   /
males. Thus, the peripherally expanding T cells would still respond to
IL-7, and the APCs used for sensitization would be unresponsive due to
a lack of a functional receptor. Although the dendritic cell yield per
animal was lower from the IL-7R/ mice than from
IL-7R+/+ animals, the phenotype was identical (Figure
6). Further, as seen in Figure
7, IL-7R/ APCs are
able to induce HY graft rejection in animals receiving a sufficient LN
inocula (25 × 106) at essentially the same rate as
thymus-bearing animals, thus establishing functionality of these APCs.
However, when an insufficient LN inocula was sensitized with enriched
IL-7R/ dendritic cells, administration of rhIL-7
resulted in significantly delayed rejection relative to mice receiving
enriched dendritic cells capable of responding to IL-7
(P = .006). Therefore, a partial loss of the effect of
IL-7 on restoration of naive responses was seen, demonstrating that the
effects of IL-7 in this model are not limited to peripherally expanding
T cells but also include modulation of APCs.
Depletion of T cells is a hallmark of a number of disease processes and is an anticipated side effect of therapeutic modalities such as cancer chemotherapy and stem cell transplantation. Although much has been learned about the pathways that lead to T-cell immune reconstitution, including the substantial degree to which thymic-independent pathways can contribute to this process, it remains unclear to what extent thymic-independent pathways can restore host immune competence. In this report, we describe a model that illustrates functional deficits in immune responses to nominal antigen after thymic-independent T-cell regeneration. Using this model, we have shown that immune competence can be restored in the absence of thymic pathways by modulation of the process of peripheral expansion by increasing T-cell inocula, by inhibiting programmed cell death, and by cytokine administration. A number of interesting findings emerge from these experiments. First, in this murine model, the number of T cells required to restore host immune competence (25 × 106 LN cells or approximately 20 × 106 T cells) is approximately equal to 10% of the total T-cell number estimated for an intact mouse.52 Although the number required would be likely to vary depending on the antigen and the precursor frequency of the antigen-specific T cells within the inocula, these results illustrate the degree of redundancy that exists within the immune system. What remains unclear is whether this number is relative and must be increased proportionally to restore immune competence in larger hosts (such as humans) or whether this represents an absolute number of T-cell receptor specificities required for response to diverse environmental antigens. Second, the finding that restoration of immune responses can occur in the absence of newly developed T-cell receptor specificities via thymic pathways emphasizes that the deficits in T-cell receptor repertoire that result from peripheral expansion are relative rather than absolute. Thus, by improving the efficiency of peripheral expansion by inhibiting cell death and, potentially, by increasing APC capacity, substantially lower numbers of antigen-specific T cells may be adequate for successful induction of immune responses. Third, the data show a clear role for programmed cell death in limiting immune responses after thymic-independent peripheral expansion. Although this is suggested by the finding of increased annexin V staining on peripherally expanded T cells manipulated ex vivo, it is more definitively shown by the increased number of T cells derived from hbcl-2 transgenic inocula and, more importantly, by restoration of immune responses to nominal antigen by constitutive bcl-2 transgene expression. Thus, peripherally expanding T cells that would otherwise be lost to apoptotic cell death are rescued and, therefore, contribute to the reconstitution of the T-cell pool. However, restoration of immune responses by inhibition of apoptosis appears to be confined to the setting of recall responses indicating important differences in the requirements for induction of responses to recall and naive antigens after thymic-independent T-cell reconstitution. This phenomenon may partially explain the restoration of recall responses and protection from opportunistic infections, which has been observed during immune reconstitution of HIV-infected patients53-56 and cannot be clearly attributed to restoration of T-cell repertoire via thymic-dependent pathways.57 The widely accepted model for T-cell death holds that there are 2 primary pathways that ultimately end in apoptosis.58,59 The active process requires T-cell receptor stimulation, is mediated by Fas ligand and other tumor necrosis factor (TNF) family molecules, occurs at effective cytokine concentrations, and is inefficiently inhibited by bcl-2. The passive pathway, such as occurs with insufficient cytokine support, is strongly inhibited by bcl-2. Based on this model, our results present a potential paradox. The degree of activation of peripherally expanded T cells and the requirement for antigen would suggest that the limitations in immune responses observed in our experiments are the result of active apoptosis of peripherally expanding T cells. These models would predict that bcl-2 would be unable to restore immune responses in this setting. A potential explanation for this finding may be that there is some degree of passive cell death occurring during peripheral expansion due to competition for limiting growth factors. Alternatively, it has been reported that up-regulation of bcl-2 family members can lead to inhibition of Fas-mediated cell death in some situations.60,61 Whether inhibition of the processes involved in active cell death would have a more potent effect on immune responses in these models is currently under study. Interleukin-7 is a cytokine with extremely diverse and potent effects on T- and B- lineage cells. It is uniquely suited to restore immune competence after TCD because of its effects on multiple pathways of T-cell regeneration. The effects of IL-7 on thymopoiesis have been well characterized. Emerging data suggest that IL-7 may also have effects on extrathymic T-cell differentiation (K. Weinberg, written communication, 2000) potentially providing a partial explanation for the restoration of responses to HY antigen observed in some animals when rhIL-7 is administered without primed T cells. In addition, IL-7 has been shown to induce proliferation of naive T cells without altering the phenotype.62 However, the effects of IL-7 on mature T-cell populations in vivo are less well characterized and the ability for this cytokine to enhance immune reconstitution via thymic-independent peripheral expansion has not been reported previously. In this report we show that IL-7 potently modulates the peripheral expansion pathway to T-cell regeneration. This action appears to be multifactorial and due to effects on expanding T cells as well as effects on APC populations. Modulation of APCs by IL-7 has not been reported and the mechanisms of this effect are currently being investigated in more detail (K. Komschlies, in preparation). Importantly, we have found IL-7 to be unique among the T-cell-active cytokines tested in inducing peripheral expansion.63 This finding raises the possibility that endogenously produced IL-7 could also play a role in regulating this process during T-cell regeneration and thus contribute to T-cell homeostasis. Indeed, it is well known that TCD leads to enhanced expansion of mature T cells and preliminary results from our laboratory (Fry et al, manuscript submitted) in patients with HIV and studies by others64 have shown elevated serum IL-7 levels in patients with TCD. Interleukin-7 may have potential application as a biologic modifier in a number of clinical situations. First, after stem cell transplantation, prolonged lymphodepletion results in susceptibility to infection that contributes to transplant-related morbidity, especially in allogeneic transplants. Administration of IL-7 during this period would be predicted to lead to more rapid lymphocyte recovery, improved responses to foreign antigens, and a reduction in mortality from infections in the posttransplant period. Although there are clearly inherent differences between our model, which uses antibody depletion of T cells, and a stem cell transplantation model that uses cytotoxic conditioning regimens, there are many similarities including the reliance on peripheral expansion and the contribution of residual T cells to immune reconstitution. Thus, these findings are likely to be relevant to clinical transplantation. Second, although there has been success in substantially reducing viral load in patients with HIV infection, a proportion of patients fail to show complete immunologic recovery and discontinuation of antiretroviral agents results in eventual rebound in the viral load. Therefore, one of the current challenges in the treatment of HIV lies in restoring immune responses to the virus. IL-7, with its ability to restore both recall and naive responses after TCD, has the potential to be an excellent adjuvant in this setting. Whether activation of resting T cells will contribute to infection of new cells is not known. Lastly, immunotherapeutic approaches to cancer treatment will probably be most effective in the eradication of minimal residual disease remaining after standard cytotoxic therapy. However, as indicated by these findings, the TCD that results will likely provide a major barrier to the success of these approaches. Immune adjuvants such as IL-7 might vastly improve the results of cancer immunotherapy trials that are attempted in the setting of TCD.
We would like to thank Dr Scott Durum for his careful review of this manuscript.
Submitted June 20, 2000; accepted November 7, 2000.
The contents of this publication do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This project was funded in whole or part with funds from the National Cancer Institute, National Institutes of Health, under contract no. NO1-CO-56000. By acceptance of this article, the publisher or recipient acknowledges right of the U.S. Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Terry J. Fry, Bldg 10, Rm 13N240, MSC 1928, 10 Center Dr, Bethesda, MD, 20892-1928; e-mail: tf60y{at}nih.gov.
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Top
Abstract
Introduction
, n = 4) when compared to mice receiving no LN inocula (
,
n = 5). When the LN cell dose is increased to
10 × 106, there is rejection in all mice but the rate of
graft rejection remains delayed (
, n = 5). At a dose of
25 × 106 LN cells (
, solid line, n = 5), graft
rejection occurs at a rate analogous to thymus-bearing control animals
(
, dashed line, n = 6) also receiving primed inocula. Note the
modest effect of the primed inocula when this group is compared to
thymus-bearing animals receiving an unprimed inocula (
, dashed line,
n = 5). (B) To assess primary immune responses, TXY/TCD mice were
given graded numbers of LN cells from syngeneic females naive to male
antigen via tail vein. The mice were then sensitized by intraperitoneal
injection of 1 × 105 enriched male dendritic cells from
male splenocytes as described in "Materials and methods." These
cells express B7-1, B7-2, CD11c, and major histocompatibility complex
(MHC) class II and represent 50% to 60% of the cells injected in all
experiments. Twenty-one days after LN cell transfer and enriched male
dendritic cell sensitization, the mice were grafted with male tail skin
as before and observed for rejection. As with the recall responses,
mice receiving 1 × 106 naive cells were unable to reject
HY-disparate skin grafts (
, n = 7) completely restored
responses so that rejection occurred at similar rate to thymus-bearing
control groups receiving enriched dendritic cells (
immune regulation in a dynamic and unpredictable antigenic environment.
Annu Rev Immunol.
1999;17:221253.
/