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Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
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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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In addition to the factors that control cell survival, mature T cells are subject to regulation by homeostatic mechanisms that maintain the overall size of the T cell pool at a constant level (15, 16, 17). Hence, expansion of the T cell pool during a strong immune response is followed by a death phase in which most of the recently produced effector cells perish (18, 19). Similarly, conditions of severe T cell deficiency have long been known to induce spontaneous expansion of the remaining T cells, which can eventually restore the T cell pool to near normal size without any contribution from the thymus (15, 16, 20). This type of "homeostatic" proliferation occurs when T cells are adoptively transferred into lymphopenic syngeneic nude, SCID, recombination-activating gene (RAG)4-deficient, and irradiated hosts (21, 22). Homeostatic proliferation applies to T cells with multiple specificities and occurs in the absence of deliberate Ag injection. In addition, recent experiments with MHC class I- or II-deficient mice have revealed that contact with self-MHC class I and II molecules are required for homeostatic proliferation of naive CD8+ and CD4+ cells, respectively (23, 24, 25, 26, 27, 28, 29, 30). Nevertheless, the prevailing view up to now has been that such proliferation is driven by environmental Ags (17, 20), largely based on the assumption that tolerance induction renders T cells completely unresponsive to self-Ags.
However, we and others recently have obtained strong evidence that homeostatic proliferation of naive T cells is driven by MHC molecules loaded with specific self-peptides, namely the peptides that initially induced positive selection of the T cells in the thymus (25, 27, 28). Results from two separate systems support this scenario. First, it was found that normal CD4+ cells failed to undergo efficient proliferation in syngeneic T cell (T)-depleted H2-M- mice, i.e., mice that express MHC class II H2-Ab molecules loaded mostly with a single species of self-peptide, class II-associated invariant chain peptide (CLIP) (31, 32, 33). Thus, naive CD4+ cells from wild-type C57BL/6 (B6) mice, which have been positively selected on MHC class II molecules loaded with diverse self-peptides, proliferated very poorly in H2-M- hosts, whereas naive CD4+ cells from H2-M- mice, positively selected to CLIP, proliferated efficiently in H2-M- hosts (25, 27). Second, in TAP- mice engineered to express Kb molecule loaded with specific peptides, homeostatic proliferation of naive CD8+ OT-I TCR-transgenic T cells required that the T-depleted hosts express a low-affinity peptide that previously had been shown to induce positive selection of OT-I cells in fetal thymic organ cultures (28).
Based on the above findings, we proposed that the weak TCR signals received by naive T cells making contact with self-MHC/peptide ligands are translated differently depending on the total size of the T cell pool (27). Under normal T-sufficient conditions, the signals promote prolonged survival of T cells in a resting state, but under lymphopenic conditions the TCR signals induce naive T cells to proliferate. However, why lymphocytopenia seems to augment TCR signals in residual T cells and causes these cells to enter cell cycle is still unclear. There are at least two broad possibilities. First, T cells may undergo homeostatic proliferation in response to increased availability of stimulatory factors. These factors could be either cell surface molecules, such as specific MHC/peptide ligands and costimulatory molecules on APC, or soluble factors such as cytokines that either work locally or systemically. Second, T cells could undergo proliferation because they have been liberated from constant inhibitory signals that dampen the overall accumulative signals received from continuous interaction with self-MHC/peptide ligands. Such suppressive cues could come either from direct interaction with other T cells or through a complex interaction involving a third-party cell, such as APC or stromal cells.
To examine this issue, we have investigated whether there exists a spatial requirement for T cells to undergo homeostatic proliferation, and whether homeostatic proliferation can be controlled by the presence of large numbers of "bystander" T cells with different characteristics. Data from these experiments support a model in which homeostatic proliferation is regulated through short-range T-T interactions within specific regions of the lymphoid tissues, namely the T cell zones in spleen and lymph nodes (LN).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All mice were used at 6–12 wk of age. B6 (H2b), B6.PL (H2b, Thy1.1+), and B6.Ly5.1 mice were obtained from the breeding colony at The Scripps Research Institute (La Jolla, CA ). H2-M- and H2-M-.Thy1.1 in the B6 background (backcrossed six times to B6) were bred and maintained in our animal colony. B6.FasL- (gld) mice were purchased from The Jackson Laboratory (Bar Harbor, ME). B6.H2-A- (backcrossed 20 times to B6) and CTLA-4- (backcrossed six times to B6) mice were obtained from Dr. Terry Laufer (University of Pennsylvania, Philadelphia, PA) and Dr. Craig Thompson (University of Pennsylvania), respectively. OT-II and AND TCR-transgenic mice were obtained from Dr. William Heath (Walter and Eliza Hall Institute, Melbourne, Australia) and Dr. J. Kaye (The Scripps Research Institute), respectively. CTLA-4- plus B6-mixed bone marrow (BM) chimeras were generated as recently described (34). Briefly, lethally irradiated (1000 cGy) B6.Ly5.1 mice were injected with a mixture of CTLA-4- (Thy-1.2+ Ly5.2+) and B6.PL (Thy-1.1+ Ly5.2+) T-depleted BM cells. After 8–12 wk, CTLA-4- T cells and B6.PL T cells were purified from the host LN cells and used for inhibition experiments.
Abs and cell purification
The mAbs to H2-Ab (28-16-8s), heat-stable Ag (J11d), Thy1.2 (J1j), CD4 (GK1.5 and RL172), and CD8 (3.168) have been described previously (35). CD4+ cells were purified by killing with a cocktail of anti-CD8, anti-H2-Ab, and anti-heat-stable Ag mAbs plus complement and then panning on plates coated with anti-CD4 mAbs (35).
Adoptive transfer of T cells
Small numbers (1–2 x 106/mouse) of whole LN cells or purified T cells were labeled with the intracellular fluorescent dye CFSE (Molecular Probes, Oregon) as described (36) and i.v. injected into host mice. For inhibition experiments, the CFSE-labeled "donor" cells were coinjected i.v. with large numbers (3–8 x 107 cells/mouse) of unlabeled whole LN cells or purified T cells. Host mice received a sublethal dose (600 cGy) of whole body irradiation 1 day before donor cell injection.
LN cells were treated with pertussis toxin (PTX) (List Biological Laboratories, Campbell, CA) as described (37). Briefly, cells were incubated in RPMI 1640 containing 2% FCS at 4 x 107 cells/ml with 100 ng/ml PTX at 37°C for 2 h and then washed three times with RPMI 1640 medium before use.
In vitro proliferation
Whole LN B6 cells treated with medium only or medium plus PTX were incubated at 2 x 105 cells/well with titrating doses of anti-CD3 mAb (2C11; BD PharMingen, San Diego, CA) for 2 days. Some cells were incubated with irradiated (2000 cGy) T-depleted B6, B6.bm12, B6.bm1 or B10.BR spleen cells (7 x 105 cells/well) for 3–5 days. Cultures were pulsed with 1 µCi [3H]thymidine/well 8 h before harvest.
Histological analysis
Frozen spleen and LN sections were prepared and stained as described previously (38). Briefly, freshly cut 6-µm sections were dried and fixed with acetone and stained with mAbs. For immunofluorescence, sections were stained with biotinylated RA3-6B2 (anti-B220; PharMingen) followed by PE-conjugated streptavidin (Life Technologies, Rockville, MD). For single-color immunohistochemistry, sections were stained with OX-7 (anti-Thy-1.1; BD PharMingen) followed by alkaline phosphatase (AP)-conjugated streptavidin (Jackson ImmunoResearch, West Grove, PA) and developed with AP substrate Fast Violet (Sigma, St. Louis, MO) as described (38); the sections then were counterstained with hematoxylin. For three-color staining, sections were sequentially incubated between washings with biotinylated J1j (anti-Thy-1.2) plus AP-conjugated streptavidin, followed by biotinlyated A20-1.7 (anti-Ly5.1) plus HRP-conjugated streptavidin (Jackson ImmunoResearch) followed by biotinylated RA3-6B2 plus glucose oxidase (GO)-conjugated streptavidin (Jackson ImmunoResearch). To block nonspecific binding of biotinlyated Abs, sections were treated with avidin and biotin blocking reagents (Vector Laboratories, Burlingame, CA) between each biotin and steptavidin reactions. The sections were developed with sequential incubation with substrates Fast Blue, 3-amino-9-ethylcarbazole, and the commercially available substrate for GO (GO tetranitrotetrazolium blue chloride) purchased from Vector Laboratories.
FACS analysis
Host LN and spleen cell suspensions were stained for the donor cells by standard procedures as described (35). Briefly, donor T cells were detected by staining with either biotinylated OX-7 mAb (anti-Thy1.1; BD PharMingen), J1j (anti-Thy1.2), or A20-1.7 (anti-Ly5.1). Cells then were double stained with PE-conjugated anti-CD4 (Life Technologies) mAbs and Cy5-conjugated streptavidin (Jackson ImmunResearch). Ly5.1 congenic donor cells were stained further with CyChrome-conjugated anti-CD8 mAb (BD PharMingen) to identify donor CD8+ cells. CFSE levels on donor cells are shown as histograms for gated donor CD4+ and CD8+ T cells (Thy-1+ CD4- or Ly5+ CD8+). Dead cells were excluded by staining with propidium iodide. Background staining by donor-specific mAbs was negligible (no >0.01%) in cells from control irradiated mice that did not receive any donor cells (not shown).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As described previously (27), homeostasis-driven
proliferation of naive T cells can be readily observed by adoptively
transferring small numbers of T cells into sublethally irradiated (600
cGy) syngeneic mice. Thus, in irradiated B6
(Thy-1.2+) mice injected with
106 CFSE-labeled congenic B6.PL
(Thy-1.1+) purified T cells, the proliferation of
donor T cells, as indicated by the appearance of cells with progressive
2-fold reductions in CFSE intensity, begins within 2–3 days after
injection and becomes prominent by 6–8 days after injection (Fig. 1
). A population of donor T cells with no
CFSE content, indicative of having undergone multiple rounds of cell
division, is often visible after 6 days. This population appears to
arise from expansion of donor memory T cells, as we have found
previously that a prominent CFSE-negative peak is not observed when
injected donor T cells are depleted of memory phenotype cells
(27)
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A, where a section of the
spleen from a mouse 8 days after injection shows a cluster of
CFSE+ donor cells with variable CFSE intensity in
the pals, indicating that the cells had undergone cell division.
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D). This
effect of PTX is attributable to the inactivation of GTP-binding
proteins (G proteins) by the ADP-ribosyltransferase of PTX, thereby
neutralizing the G protein-coupled chemokine receptor 7 (CCR7) that
recognizes two key chemokines for T cell trafficking: secondary
lymphoid tissue chemokine, which attracts lymphocytes onto high
endothelial venules for transmigration into the LN, and EBV-induced
molecule 1 ligand chemokine, which in conjunction with secondary
lymphoid tissue chemokine attracts T cells into the T cell zones in the
LN and spleen (37). Strikingly, CFSE-labeled PTX-treated
donor B6.Ly5.1 T cells obtained from the spleens of irradiated B6 mice
8 days after adoptive transfer remained uniformly
CFSEhigh, whereas CFSE-labeled sham-treated B6.PL
T cells that were coinjected into the same host underwent efficient
proliferation (Fig. 3A). The
inability of PTX-treated T cells to undergo homeostatic proliferation
did not appear to be attributable to a general block in the cell cycle
because these cells proliferated as efficiently as sham-treated control
T cells in vitro in response to stimulation by anti-CD3 mAb or
allogeneic spleen cells (Fig. 3B). It is important to
emphasize that despite their lack of division, the PTX-treated T cells
survived well after adoptive transfer; thus 10–20% of the injected
cells were recovered on day 8, which was similar to the recovery of
sham-treated cells in unirradiated hosts.
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were used as hosts.
LT- is required for normal development of LNs and
Peyer’s patches, and hence LT- mice lack
peripheral lymphoid tissues, except for the spleen, which is
structurally disorganized and largely devoid of discrete T cell areas
(39). After injection of CFSE-labeled B6.PL
CD4+ and CD8+ cells into
B6.LT- mice, CFSE+
donor T cells on day 8 were found in the spleen intermingled with the B
cells in the disorganized white pulp (Fig. 2B). Notably, the
Thy-1.1+ donor T cells in
B6.LT- host spleen underwent only minimal
cell division, whereas the donor T cells proliferated efficiently in
irradiated normal B6 host spleen (Fig. 4).
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We have shown previously that proliferation of donor T cells in
irradiated syngeneic hosts can be suppressed by coinjecting large
numbers of unlabeled syngeneic T cells with CFSE-labeled donor cells.
As shown here, the level of suppression is directly proportional to the
dose of coinjected "bystander" T cells: partial suppression can be
achieved by coinjecting as few as 0.5–1 x
107 bystander T cells (1–2 x
107 whole LN cells), whereas near-complete
inhibition requires higher doses (Fig. 5). Because the data discussed above
indicate that homeostatic proliferation occurs within the T cell areas
of the secondary lymphoid tissues, it was of interest to determine
whether bystander T cells must also gain entry into the T cell area to
mediate suppression. To test this idea, bystander T cells were treated
first with PTX to neutralize their ability to enter into the T cell
areas and then were coinjected with CFSE-labeled normal T cells into
irradiated syngenic mice. As shown in Fig. 6, coinjection of a large dose of B6 LN
cells (8 x 107) treated with PTX failed to
suppress proliferation of CFSE-labeled B6.PL T cells in irradiated B6
hosts, whereas sham-treated control B6 LN cells efficiently inhibited
proliferation. This finding applied not only to cells localizing in
host LNs, where PTX-treated T cells failed to gain entry, but also to
the cells in host spleens where PTX-treated T cells accumulated in
large numbers only in the red pulp; data for the spleen are shown for
Fig. 6.
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Because entry into the T cell areas of the lymphoid tissues
applies to both naive and memory cells, the question arises whether
both of these cell types have the capacity to inhibit homeostatic
proliferation of naive T cells. It is difficult to prepare large
numbers of activated or memory phenotype T cells from normal mice
because of their low abundance; there are also problems with using in
vitro-activated T cells because these cells survive poorly after
injection in vivo. In view of these problems we used T cells from adult
CTLA-4-deficient and Fas ligand (FasL)-deficient (B6.gld) mice as
bystander cells; for these two strains, the vast majority of peripheral
T cells have an activated/memory phenotype (40, 41, 42, 43, 44). The
striking finding was that coinjection of large numbers of LN cells
(7 x 107) from either
CTLA-4- or FasL- mice
failed to suppress proliferation of CFSE-labeled B6.PL
CD4+ and CD8+ cells in
irradiated B6 hosts (Fig. 7A),
whereas wild-type B6 LN cells efficiently suppressed proliferation (not
shown). Histological analysis revealed that the activated/memory
phenotype CTLA-4- and
FasL- T cells were found in all the compartments
of the secondary lymphoid organs including the T cell zones and were in
close proximity to naive T cells; CTLA-4- T
cells are shown in Fig. 2E.
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B, naive
CTLA-4- and CTLA-4+
bystander T cells from the BM chimeras were equally effective in
inhibiting homeostatic proliferation of CFSE-labeled
B6.Ly5.1+ T cells in irradiated syngeneic B6
hosts. Based on these findings, it would appear that bystander
inhibition of naive T cell homeostatic proliferation can be mediated
only by naive cells and not by activated/memory cells. Do bystander cells compete for stimulatory MHC/peptide ligands or factors?
The requirement for naive T cells to enter the T cell zones to undergo homeostatic proliferation and to suppress homeostatic proliferation of other T cells suggests that certain components of the T cell zones, e.g., dendritic and/or stromal cells, may regulate T cell homeostasis. Contact with MHC molecules on dendritic cells (DC) is likely because for CD4+ cells, exclusive expression of MHC class II molecules on DC prevents the disappearance of CD4+ cells transferred to MHC class II- hosts (11). Considering that homeostatic proliferation is driven by specific self-MHC/peptide ligands and requires T-depletion of the host, it is possible that the major driving force behind such a proliferation is the increased availability of specific self-MHC/peptide ligands on DC because of a lack of competition from bystander T cells. If this idea is correct, bystander T cells with below-normal affinity for self-MHC/peptide ligands would be unable to compete at the DC level and thus would fail to suppress homeostatic proliferation of T cells.
To test this possibility, we took advantage of the previous finding
that wild-type B6 CD4+ cells fail to undergo
efficient homeostatic proliferation in T-depleted
H2-M- hosts, which express normal levels of
syngeneic MHC class II molecules (H2-Ab) loaded
predominantly with a single species of self-peptides, CLIP (25, 27). By contrast, CD4+ cells from
H2-M- mice do undergo efficient homeostatic
proliferation in T-depleted H2-M- hosts.
Collectively, these data suggest that because of differences in the
ligands controlling positive selection, most wild-type B6
CD4+ cells display significantly lower affinity
toward CLIP+H2-Ab complex than
H2-M- CD4+ cells. Based on
these findings, we tested whether homeostatic proliferation of
H2-M- CD4+ cells in
T-depleted H2-M- hosts can be inhibited by
coinjecting large numbers (5 x 107) of
purified wild-type B6 CD4+ cells. Interestingly,
these cells mediated strong inhibition of H2-M-
CD4+ cells (Fig. 8A), implying that the
inhibitory function of bystander cells is relatively independent of the
TCR affinity of these cells for self-MHC/peptide ligands.
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B, this was indeed the case. Thus, B6
CD4+ cells suppressed homeostatic proliferation
of CD8+ cells with equal efficiency in either MHC
class II+ or II- hosts.
The bystander T cells thus have the capacity to mediate inhibition
without receiving signals through their TCR.
Even without the involvement of self-MHC/peptide ligands, bystander T
cells could mediate inhibition by sequestering other stimulatory
factors essential for cell proliferation. This raises the question
whether T cells must undergo homeostatic proliferation themselves to
serve as efficient bystander cells. Considering that bystander T cells
need to be injected in large doses (>3 x
107 cells/host), which partially restores the
overall size of the T cell pool, it is unlikely that these T cells
themselves undergo a significant level of homeostatic proliferation.
Nevertheless, a small fraction of bystander T cells might undergo
proliferation, even in hosts deficient in expression of H2-M or MHC
molecules, and this could be sufficient to inhibit homeostatic
proliferation. Hence, we tested whether TCR-transgenic T cells (AND and
OT-II), which are almost completely unable to proliferate in irradiated
hosts (Ref. 27 and our unpublished observation), can serve
as bystander T cells. This was found to be the case, as coinjection of
either AND or OT-II cells significantly suppressed proliferation of
both normal B6 CD4+ and
CD8+ cells in irradiated syngeneic hosts (Fig. 8C).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The possibility that homeostatic proliferation is driven by a surplus of systemic soluble factor(s) was tested using PTX-treated T cells, with the rationale that these cells will still be able to respond to systemic factors even though they no longer migrate into the LNs or into the T cell compartments of the spleen. Strikingly, PTX-treated T cells failed to undergo proliferation in lymphopenic hosts despite their entry into the non-T cell compartments of the spleen, namely the red pulp areas that contain numerous MHC+ cells. Because PTX-treated T cells survived well in vivo and were unimpaired in their ability to undergo proliferation when stimulated through the TCR in vitro, the failure of PTX-treated T cells to undergo homeostatic proliferation in lymphopenic hosts presumably reflected that these cells are unable to enter the T cell compartments. The requirement for entry into the T cell compartments also applied for the bystander cells that mediate inhibition of homeostatic proliferation. Thus, in contrast to normal T cells, coinjection of large numbers of PTX-treated bystander naive T cells failed to block homeostatic proliferation of untreated normal naive T cells in lymphopenic hosts. This was apparent despite the finding that injected PTX-treated T cells engrafted efficiently and persisted in large numbers in the blood, BM, and the splenic red pulp of the hosts. Considering the fact that G proteins are coupled with a wide spectrum of receptors, it should be mentioned that we cannot completely rule out the possibility that the effect observed with PTX treatments is due to neutralization of receptors directly involved in homeostatic proliferation. Despite this caveat, the above findings collectively argue against the idea that homeostatic proliferation is induced by increased availability of some soluble factors that work systemically in a hormone-like fashion throughout the body.
The finding that naive T cells must enter specific T cell compartments
to undergo homeostatic proliferation also suggests that the DC resident
in this site are the primary APC that present self-MHC/peptide ligands
to drive this response. The idea that DC are the crucial APC for
homeostatic proliferation is in accord with the findings that long-term
survival of naive CD4+ cells can be maintained by
exclusive expression of MHC class II molecules only on DC
(11). On this point, it is notable that homeostatic
proliferation failed to occur efficiently in
LT- mice. Although this finding could be a
reflection of various defects in these mice, the finding is of interest
because the disorganized white pulp of LT-
mice shows a marked reduction in DC (45). Collectively,
these data suggest that homeostatic proliferation in T cell compartment
is largely under the control of DC. Whether other cell types, e.g.,
stromal cells, are involved is still unclear. Macrophages and B cells
are probably not necessary because macrophages are rare in T cell
compartments and homeostatic proliferation can occur in B
cell-deficient mice, e.g., in RAG-
mice.
Because homeostatic proliferation is directed to specific self-MHC/peptide ligands, the onset of proliferation in T-deficient hosts may be initiated as the result of decreased "congestion" around the DC. We assessed this possibility by determining whether bystander inhibition of homeostatic proliferation could be mediated by CTLA-4- and FasL- T cells; these cells were able to efficiently migrate into the T cell compartments and therefore were presumably able to create congestion around DC. Significantly, however, coinjection of large doses of activated/memory phenotype CTLA-4- and FasL- bystander T cells did not inhibit homeostatic proliferation of naive T cells; by contrast, naive phenotype CTLA-4- bystander T cells did efficiently inhibit homeostatic proliferation. Despite the concern that activate/memory phenotype CTLA-4- and FasL- T cells may not represent real memory T cells in terms of their homeostasis requirements, these data nevertheless strengthen the view that homeostasis of naive and memory T cells is independently regulated (46). In support of this idea, we have recently observed that homeostatic proliferation of normal B6 memory phenotype T cells cannot be suppressed by coinjecting large numbers of only naive phenotype bystander T cells (unpublished observation). For CTLA-4- T cells, it is of particular interest that naive phenotype CTLA-4- T cells shared the capacity of normal naive T cells to inhibit bystander proliferation of naive T cells. This finding is thus against the idea that homeostatic proliferation of naive T cells is under the control of CTLA-4 molecule (44). Whether CTLA-4 influences homeostatic proliferation of memory phenotype cells has yet to be studied.
The notion that bystander inhibition of homeostatic proliferation reflects competition for MHC/peptide ligands on APC predicts that bystander inhibition would be reduced if the T cells used as bystanders had limited affinity for the ligands inducing homeostatic proliferation. Three findings are against this idea. First, homeostatic proliferation of H2-M- CD4+ cells to CLIP/H2-Ab in H2-M- hosts was efficiently blocked by normal B6 CD4+ cells, i.e., by cells that presumably have very limited affinity for CLIP/H2-Ab. Second, the capacity of normal B6 CD4+ cells to inhibit bystander proliferation of CD8+ cells applied in MHC I+II- hosts, i.e., hosts where the bystander CD4+ cells failed to see MHC II molecules. Third, T cells with only very low affinity for self-MHC/peptide ligands, i.e., particular transgenic T cells that exhibit little or no capacity to undergo homeostatic proliferation in T-deficient hosts, were nevertheless able to mediate efficient bystander inhibition of normal T cells. These findings, especially the data with MHC I+II- hosts, imply that bystander inhibition does not depend on TCR ligation.
Although the above data argue that bystander inhibition does not reflect competition for MHC/peptide ligands on APC, there may still be competition for other ligands, e.g., cell-associated or soluble factors released from APC in the T cell zones. For soluble factors, it is possible that cytokines known to promote survival of naive T cells in vitro, such as IL-4, IL-6, and IL-7 (47, 48, 49), are involved in regulating naive T cell homeostasis. This possibility is currently under investigation.
An alternative idea is that bystander inhibition is mediated as the result of direct T-T interactions in the T cell zone. Based on the data presented here, such inhibition would be MHC independent and requires T-T interactions at the level of naive T cells. This notion hinges on the assumption that interactions between complementary molecules on T cells during T-T contact inhibit proliferation. Currently, there is little if any direct data that favors or refutes this possibility.
Note added in proof.
While this manuscript was in press, Schluns et al. reported that efficient homeostatic proliferation fails to occur in syngeneic IL-7-deficient hosts, thus strongly implicating that homeostasis of naive T cells is regulated mainly by IL-7 50 . Accordingly, homeostatic proliferation is presumably induced by increased availability of IL-7 in T-depleted hosts and blocked by the removal of the excess IL-7 by the bystander cells.
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Acknowledgments |
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Footnotes |
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2 Current address: Department of Anatomy, Seoul National University, College of Medicine, Seoul, 110-799, Korea.
3 Address correspondence and reprint requests to Dr. Charles D. Surh, Department of Immunology, IMM26, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037.
4 Abbreviations used in this paper: RAG, recombination activating gene; B6, C57BL/6; LN, lymph nodes; LT, lymphotoxin; PTX, pertussis toxin; AP, alkaline phosphatase; GO, glucose oxidase; G protein, GTP-binding protein; FasL, Fas ligand; BM, bone marrow; DC, dendritic cells; CLIP, class II-associated invariant chain peptide; pals, periarteriolar lymphocyte sheath.
Received for publication September 21, 2000. Accepted for publication November 21, 2000.
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References |
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T cells in secondary lymphoid organs. J. Exp. Med. 177:891.This article has been cited by other articles:
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T. Zaft, A. Sapoznikov, R. Krauthgamer, D. R. Littman, and S. Jung CD11chigh Dendritic Cell Ablation Impairs Lymphopenia-Driven Proliferation of Naive and Memory CD8+ T Cells J. Immunol., November 15, 2005; 175(10): 6428 - 6435. [Abstract] [Full Text] [PDF]
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J. Su, R. E. Berg, S. Murray, and J. Forman Thymus-Dependent Memory Phenotype CD8 T Cells in Naive B6.H-2Kb-/-Db-/- Animals Mediate an Antigen-Specific Response against Listeria monocytogenes J. Immunol., November 15, 2005; 175(10): 6450 - 6457. [Abstract] [Full Text] [PDF]
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 L. Gattinoni, S. E. Finkelstein, C. A. Klebanoff, P. A. Antony, D. C. Palmer, P. J. Spiess, L. N. Hwang, Z. Yu, C. Wrzesinski, D. M. Heimann, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells J. Exp. Med., October 3, 2005; 202(7): 907 - 912. [Abstract] [Full Text] [PDF]
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K. A. Fortner and R. C. Budd The Death Receptor Fas (CD95/APO-1) Mediates the Deletion of T Lymphocytes Undergoing Homeostatic Proliferation J. Immunol., October 1, 2005; 175(7): 4374 - 4382. [Abstract] [Full Text] [PDF]
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 S. P Hickman and L. A Turka Homeostatic T cell proliferation as a barrier to T cell tolerance Phil Trans R Soc B, September 29, 2005; 360(1461): 1713 - 1721. [Abstract] [Full Text] [PDF]
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A. M. Marleau and N. Sarvetnick T cell homeostasis in tolerance and immunity J. Leukoc. Biol., September 1, 2005; 78(3): 575 - 584. [Abstract] [Full Text] [PDF]
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N. Bosco, F. Agenes, and R. Ceredig Effects of Increasing IL-7 Availability on Lymphocytes during and after Lymphopenia-Induced Proliferation J. Immunol., July 1, 2005; 175(1): 162 - 170. [Abstract] [Full Text] [PDF]
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A. Gruber and T. Brocker MHC Class I-Positive Dendritic Cells (DC) Control CD8 T Cell Homeostasis In Vivo: T Cell Lymphopenia as a Prerequisite for DC-Mediated Homeostatic Proliferation of Naive CD8 T Cells J. Immunol., July 1, 2005; 175(1): 201 - 206. [Abstract] [Full Text] [PDF]
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B. Min, H. Yamane, J. Hu-Li, and W. E. Paul Spontaneous and Homeostatic Proliferation of CD4 T Cells Are Regulated by Different Mechanisms J. Immunol., May 15, 2005; 174(10): 6039 - 6044. [Abstract] [Full Text] [PDF]
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I. Messaoudi, J. LeMaoult, J. A. Guevara-Patino, B. M. Metzner, and J. Nikolich-Zugich Age-related CD8 T Cell Clonal Expansions Constrict CD8 T Cell Repertoire and Have the Potential to Impair Immune Defense J. Exp. Med., November 15, 2004; 200(10): 1347 - 1358. [Abstract] [Full Text] [PDF]
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B. A. Sullivan, L. M. Reed-Loisel, G. J. Kersh, and P. E. Jensen Homeostatic Proliferation of a Qa-1b-Restricted T Cell: A Distinction between the Ligands Required for Positive Selection and for Proliferation in Lymphopenic Hosts J. Immunol., November 15, 2004; 173(10): 6065 - 6071. [Abstract] [Full Text] [PDF]
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M. A. Mihalyo, A. D. H. Doody, J. P. McAleer, E. C. Nowak, M. Long, Y. Yang, and A. J. Adler In Vivo Cyclophosphamide and IL-2 Treatment Impedes Self-Antigen-Induced Effector CD4 Cell Tolerization: Implications for Adoptive Immunotherapy J. Immunol., May 1, 2004; 172(9): 5338 - 5345. [Abstract] [Full Text] [PDF]
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 B. Min, G. Foucras, M. Meier-Schellersheim, and W. E. Paul Spontaneous proliferation, a response of naive CD4 T cells determined by the diversity of the memory cell repertoire PNAS, March 16, 2004; 101(11): 3874 - 3879. [Abstract] [Full Text] [PDF]
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Q. Ge, A. Bai, B. Jones, H. N. Eisen, and J. Chen Competition for self-peptide-MHC complexes and cytokines between naive and memory CD8+ T cells expressing the same or different T cell receptors PNAS, March 2, 2004; 101(9): 3041 - 3046. [Abstract] [Full Text] [PDF]
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T. Schuler, G. J. Hammerling, and B. Arnold Cutting Edge: IL-7-Dependent Homeostatic Proliferation of CD8+ T Cells in Neonatal Mice Allows the Generation of Long-Lived Natural Memory T Cells J. Immunol., January 1, 2004; 172(1): 15 - 19. [Abstract] [Full Text] [PDF]
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W. C. Kieper, J. T. Burghardt, and C. D. Surh A Role for TCR Affinity in Regulating Naive T Cell Homeostasis J. Immunol., January 1, 2004; 172(1): 40 - 44. [Abstract] [Full Text] [PDF]
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 A. L. Cornish, M. M. Chong, G. M. Davey, R. Darwiche, N. A. Nicola, D. J. Hilton, T. W. Kay, R. Starr, and W. S. Alexander Suppressor of Cytokine Signaling-1 Regulates Signaling in Response to Interleukin-2 and Other {gamma}c-dependent Cytokines in Peripheral T Cells J. Biol. Chem., June 13, 2003; 278(25): 22755 - 22761. [Abstract] [Full Text] [PDF]
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Z. Kurepa, J. Su, and J. Forman Memory Phenotype of CD8+ T Cells in MHC Class Ia-Deficient Mice J. Immunol., June 1, 2003; 170(11): 5414 - 5420. [Abstract] [Full Text] [PDF]
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B. Martin, C. Bourgeois, N. Dautigny, and B. Lucas On the role of MHC class II molecules in the survival and lymphopenia-induced proliferation of peripheral CD4+ T cells PNAS, May 13, 2003; 100(10): 6021 - 6026. [Abstract] [Full Text] [PDF]
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T. Barthlott, G. Kassiotis, and B. Stockinger T Cell Regulation as a Side Effect of Homeostasis and Competition J. Exp. Med., February 17, 2003; 197(4): 451 - 460. [Abstract] [Full Text] [PDF]
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C. T. Moses, K. M. Thorstenson, S. C. Jameson, and A. Khoruts Competition for self ligands restrains homeostatic proliferation of naive CD4 T cells PNAS, February 4, 2003; 100(3): 1185 - 1190. [Abstract] [Full Text] [PDF]
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A. E. Troy and H. Shen Cutting Edge: Homeostatic Proliferation of Peripheral T Lymphocytes Is Regulated by Clonal Competition J. Immunol., January 15, 2003; 170(2): 672 - 676. [Abstract] [Full Text] [PDF]
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M. S. Cabatingan, M. R. Schmidt, R. Sen, and R. T. Woodland Naive B Lymphocytes Undergo Homeostatic Proliferation in Response to B Cell Deficit J. Immunol., December 15, 2002; 169(12): 6795 - 6805. [Abstract] [Full Text] [PDF]
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M. H. Yen, N. Lepak, and S. L. Swain Induction of CD4 T Cell Changes in Murine AIDS Is Dependent on Costimulation and Involves a Dysregulation of Homeostasis J. Immunol., July 15, 2002; 169(2): 722 - 731. [Abstract] [Full Text] [PDF]
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J. T. Tan, B. Ernst, W. C. Kieper, E. LeRoy, J. Sprent, and C. D. Surh Interleukin (IL)-15 and IL-7 Jointly Regulate Homeostatic Proliferation of Memory Phenotype CD8+ Cells but Are Not Required for Memory Phenotype CD4+ Cells J. Exp. Med., June 17, 2002; 195(12): 1523 - 1532. [Abstract] [Full Text] [PDF]
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R. S. McHugh and E. M. Shevach Cutting Edge: Depletion of CD4+CD25+ Regulatory T Cells Is Necessary, But Not Sufficient, for Induction of Organ-Specific Autoimmune Disease J. Immunol., June 15, 2002; 168(12): 5979 - 5983. [Abstract] [Full Text] [PDF]
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S. Kimmig, G. K. Przybylski, C. A. Schmidt, K. Laurisch, B. Mowes, A. Radbruch, and A. Thiel Two Subsets of Naive T Helper Cells with Distinct T Cell Receptor Excision Circle Content in Human Adult Peripheral Blood J. Exp. Med., March 18, 2002; 195(6): 789 - 794. [Abstract] [Full Text] [PDF]
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Z. Dai and F. G. Lakkis Cutting Edge: Secondary Lymphoid Organs Are Essential for Maintaining the CD4, But Not CD8, Naive T Cell Pool J. Immunol., December 15, 2001; 167(12): 6711 - 6715. [Abstract] [Full Text] [PDF]
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J. Geginat, F. Sallusto, and A. Lanzavecchia Cytokine-driven Proliferation and Differentiation of Human Naive, Central Memory, and Effector Memory CD4+ T Cells J. Exp. Med., December 10, 2001; 194(12): 1711 - 1720. [Abstract] [Full Text] [PDF]
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B. R. Lawson, S. I. Koundouris, M. Barnhouse, W. Dummer, R. Baccala, D. H. Kono, and A. N. Theofilopoulos The Role of {alpha}{beta}+ T Cells and Homeostatic T Cell Proliferation in Y-Chromosome-Associated Murine Lupus J. Immunol., August 15, 2001; 167(4): 2354 - 2360. [Abstract] [Full Text] [PDF]
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Q. Ge, D. Palliser, H. N. Eisen, and J. Chen Homeostatic T cell proliferation in a T cell-dendritic cell coculture system PNAS, March 5, 2002; 99(5): 2983 - 2988. [Abstract] [Full Text] [PDF]
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J. T. Tan, E. Dudl, E. LeRoy, R. Murray, J. Sprent, K. I. Weinberg, and C. D. Surh IL-7 is critical for homeostatic proliferation and survival of naive T cells PNAS, July 17, 2001; 98(15): 8732 - 8737. [Abstract] [Full Text] [PDF]
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