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2Michael Heidelberger Division of Immunology, Department of Pathology and Kaplan Comprehensive Cancer Center, New York University Medical Center, New York, NY 10016
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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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Single positive T cells exit the thymus and populate peripheral tissues. Stimulation of these naive T cells with the Ag in the periphery leads to clonal expansion and the generation of long-lived memory T cells. The requirements for long-term survival and maintenance of memory T cells are controversial. Some studies support the requirement of Ag (7, 8), whereas in others no requirement for Ag was observed (9, 10). The maintenance of memory T cells may be mediated in a nonspecific manner, by type 1 IFNs that can induce nonspecific proliferation of recently activated T cells in vivo (11). Ag-induced expansion of memory T cells may be stronger and more rapid than that of naive T cells (12, 13). Given these Ag-specific and nonspecific proliferative advantages of memory T cells, and the relatively small influence the thymus plays in the maintenance of the adult peripheral T cell repertoire (14), one would expect the peripheral T cell repertoire to become dominated by certain TCRs that are chronically stimulated. However, this does not occur, partly due to the fact that the extensive expansion following encounter with Ag is followed by a reduction of the Ag-specific T cell pool (15, 16), and partly due to a long, and perhaps indefinite, survival of naive T cells in the absence of Ag (12, 17, 18).
What is the mechanism of persistence of naive T cells in the periphery? Do recent thymic emigrants need a signal to either enter the periphery or survive until encountering Ag? Are there any weak contacts between TCRs and self peptide-MHC molecules in the maintenance of naive T cells in the peripheral lymphoid organs? These issues are unresolved, and only recently the question of a potential requirement for peripheral MHC class II expression for CD4+ cell maintenance was addressed by grafting wild-type (MHC class II-positive) fetal thymus into MHC class II knockout mice (19). It was concluded that interactions between TCR and class II molecules were required for long-term maintenance of the CD4+ cell pool, but not for their repopulation and short-term survival in the periphery. It is becoming increasingly clear, however, that physiology of CD4+ and CD8+ cells is differentially regulated at various stages of maturation. Thus, mechanisms of thymic positive selection are most likely different for CD4+ and CD8+ cells, as overexpression of Bcl-2 transgene induces selection of CD8+, but not of CD4+ cells (20). Jak3 deficiency affects to a lesser extent thymic selection and/or peripheral repopulation of CD4+ than of CD8+ cells (21, 22, 23). The mechanisms of limiting the Ag-induced clonal expansion are also different: CD4+ cells use predominantly Fas-Fas ligand interaction, whereas most CD8+ cells use TNF-TNF receptor interaction (24). Based on these differences apparent in other stages of CD4+ and CD8+ T cell differentiation, we wondered whether peripheral repopulation by CD4+ and CD8+ recent thymic emigrants might also be different. We therefore investigated whether peripheral accumulation of CD8+ T cells may be dependent on peripheral MHC class I expression by grafting ß2m-/- recipient mice with wild-type (MHC class I-positive) thymic epithelium.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Neonatal C57BL/6 thymi were cultured for 5 days on
sponge-supported filters in RPMI media supplemented with 10% FCS, 50
µM 2-ME, and 1.35 mM deoxyguanosine, as described (25). After 5 days
of culture, thymi were placed under the left kidney capsule of
ß2m-/- mice (C57BL/6 background;
Taconic Farms, Germantown, NY). Mice were allowed to recover, and after
4 to 16 wk were sacrificed for analysis. Graft acceptance was verified
by inspection, and only mice with visibly accepted graft were included
in the study. In some experiments, mice were injected with 1 x
106 live P815 or EL4 cells s.c. 4 wk after thymus grafting,
and boosted with 1 x 107 irradiated cells i.p. 8 wk
postgrafting. Alternatively, 3 x 107
TCR-
-/- (mice obtained from Dr. Littman, NYU Medical
Center, New York, NY) spleen cells were injected at both 4 and 8 wk
postgrafting. Analysis was performed 5 days after second injection.
Flow-cytometry analysis
For detection of H-2Kb, thymocytes were
incubated with Y3 mAb-containing hybridoma supernatant, followed by
FITC-labeled goat anti-mouse Ig (Southern Biotechnology Associates,
Birmingham, AL). For two-color analysis, cells were stained with either
a combination of phycoerythrin-conjugated anti-CD8 (53-6.7;
PharMingen, Costa Mesa, CA) and FITC-conjugated anti-TCR ß-chain
(H57-597, prepared in our laboratory), or phycoerythrin-conjugated
anti-CD4 (GK1.5; Becton Dickinson, Mounain View, CA) and
FITC-conjugated anti-CD8 (3.168, prepared in our laboratory). After
the final incubation for 30 min at 4°C with Abs, cells were washed
and fixed with 1% paraformaldehyde, and analyzed using
FACScan and CellQuest software (Becton Dickinson).
Generation of alloreactive cytotoxicity
Thymocytes were incubated at 4 x 106/well (24-well plate) with 5 x 105 irradiated (10,000 rad) P815 cells in the presence of exogenous IL-2 (5% rat Con A supernatant). Spleen cells (30 x 106) were incubated with 2 x 106 irradiated (10,000 rad) P815 cells in an upright T25 flask. Five days later, target cells (P815) were labeled with 51Cr for 1 h, washed, and plated at 1 x 104/well in 96-well round-bottom plates. Five-day cultured effector cells were added at different ratios, as indicated in the figures. After 4-h incubation at 37°C, 100 µl of supernatant was harvested, and the amount of 51Cr released was measured.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Neonatal thymi from wild-type
(ß2m+/+) mice, depleted of endogenous
bone marrow-derived cells by deoxyguanosine treatment (25), were
grafted under the kidney capsule of ß2m-/-
mice. Mice were left to recover for 4 or 8 wk, since thymocytes need at
most 3 to 4 wk to complete their development in the thymus and exit to
the periphery (26). As expected, ß2m-/-
thymocyte precursors populated the ß2m+/+
thymus, as determined by H-2Kb staining (Fig. 1
). H-2Kb staining was used
to distinguish host and donor cells because small levels of
H-2Db are expressed in ß2m-/-
mice (3). The percentage of CD8+ cells expressing high
levels of ß TCR in the transplanted
(ß2m+/+) thymus was significantly higher than
that found in endogenous (ß2m-/-) thymus of
the same animals, or in nongrafted ß2m-/-
mice, and equal to that found in wild-type
ß2m+/+ thymus (Fig. 2). Phenotypic maturation of
CD8+TCRhigh cells was accompanied by
acquisition of cytotoxic function (Fig. 3), eliminating the possibility that
increased number of CD8+TCRhigh cells is due to
selective overrepresentation of
CD4+CD8+TCRhigh subset (27) in the
grafted ß2m+/+ thymus. Therefore,
ß2m-/- thymocyte precursors can populate
ß2m+/+ thymus graft and differentiate into
functionally competent CD8+ cells.
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Despite the successful reconstitution of thymic
CD8+ compartment, there was no significant increase of
CD8+ cells in the spleens (Fig. 4A), lymph nodes (data
not shown), or peripheral blood (data not shown) of transplanted mice.
This finding was obtained irrespective of whether the analysis was
performed at 4, 8, or 16 wk after thymus grafting. In addition to
conventional TCR-ß CD8+ T cells, CD8 molecule is
expressed by other cell types in the spleen, such as NK cells (28),
TCR-
T cells (29), or dendritic cells (30), but as an
homodimer, whereas conventional thymus-dependent CD8+ T
cells express ß heterodimer. Thus, immunofluorescence analysis
using CD8ß-specific mAb should be more specific for bona fide
TCR-ß CD8+ cells. Indeed, the background staining of
0.5 to 1% found with CD8-specific Ab in
ß2m-/- spleens is even lower (Fig. 4A). However, even staining using CD8ß-specific mAb
failed to reveal any significant difference between the proportion of
CD8+ cells in unmanipulated or thymus-grafted
ß2m-/- mice (Fig. 4A).
Flow-cytometry data were supported by functional assays showing absence
of cytotoxic activity in spleens of grafted
ß2m-/- mice (Fig. 4B). In
contrast, same conditions of stimulation were efficient in priming
control, wild-type C57BL/6 spleen cells. Thus, CD8+ cells
that matured in ß2m+/+ thymus grafts failed
to seed the periphery of ß2m-/-
mice.
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A possible explanation for the absence of CD8+ T
cells in the periphery may be a potential failure of the grafted
ß2m+/+ thymus to export mature
ß2m-/- T cells. To determine whether
CD8+ cells were exported by the grafted thymus, we used the
fact that antigenic stimulation leads to vigorous in vivo expansion of
CD8+ T cells (31). Although there is a drastic reduction of
CD8+ cells in ß2m-/- mice (3, 4), the presence of small numbers of CD8+ cells is visible
following injection of allogeneic ß2m+/+
tumors (32, 33). We reasoned that if there is a low, but steady supply
of naive short-lived CD8+ cells from grafted
ß2m+/+ thymus to the periphery, the
reconstitution of CD8+ compartment by
ß2m+/+ tumor injection should be
significantly better in grafted mice. This was indeed the case, as
almost complete reconstitution of functional peripheral
CD8+ compartment was observed in grafted mice injected with
live P815 cells, compared with the limited extent of CD8+ T
cell enrichment in nongrafted ß2m-/- mice
(Fig. 5). In both grafted and nongrafted
ß2m-/- mice, CD8+ cells most
likely proliferated in response to injected tumor cells. Assuming that
rates of proliferation in grafted and nongrafted
ß2m-/- mice were similar (CD8+
cell lines established from grafted and nongrafted mice expand to a
similar extent; data not shown), the dramatic difference in
CD8+ T cell compartment reconstitution between grafted and
nongrafted mice can only be explained by different number of precursor
CD8+ cells that reached the site of tumor injection.
Collectively, these findings demonstrate that
ß2m-/- CD8+ cells, which have
developed in the ß2m+/+ thymus, exited the
grafted thymus and circulated through the periphery, but failed to
accumulate in the secondary lymphoid organs in the absence of
peripheral MHC class I expression.
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To eliminate the contribution of Ag-driven CD8+ T
cell proliferation, we injected ß2m+/+
thymus-grafted ß2m-/- mice with syngeneic
ß2m+/+ cells. Either TCR--/-
spleen cells, or EL4 tumor cells were injected, and both have partially
restored the peripheral T cell compartment (Fig. 6). The reconstitution is much less
dramatic than the one observed after P815 injection, most likely due to
absence of expansion. EL4 cells were more efficient in reconstituting
the repertoire, probably because of their permanent presence (slow
growing inguinal tumors were evident in recipients), whereas
TCR--/- cells were quickly rejected, as suggested by
virtual absence of MHC class I-positive cells in recipient spleens 5
days after injection (data not shown). In separate preliminary
experiments, no enrichment of peripheral CD8+ detectable by
FACS staining could be obtained by syngeneic cell injection of
unmanipulated ß2m-/- mice (data not shown),
suggesting that the observed CD8+ T cell reconstitution was
specifically due to emigrants from the thymus graft. These results
demonstrate that presence of syngeneic ß2m+/+
cells in the periphery allows accumulation of CD8+ cells
selected in the grafted thymus.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-/- spleen cells) of injected cells. The
requirement for MHC class I for the maintenance of peripheral
CD8+ T cell pool is also supported by findings in two other
studies, using systems different from ours. In Bcl-2 transgenic mice
bred to ß2m-/- background, the presence of
the Bcl-2 transgene eliminated the requirement for MHC class I
for positive selection of CD8+ T cells in the
thymus (20). However, despite efficient reconstitution of
CD8+TCRhigh thymic compartment, no significant
increase of peripheral CD8+ cells was observed. In another
study, adoptively transferred MHC class I-restricted TCR-transgenic
cells failed to repopulate the periphery of recipients lacking
restricting MHC class I allele (34).
Although thymus grafts were on average 5 to 10 times smaller than
endogenous thymi, the numbers of CD8+ T cells expected to
exit the grafts should have been detected easily by the assays used in
this study. Studies on the kinetics of thymopoiesis demonstrated that 3
to 4 wk are sufficient for complete restoration of all thymocyte
subsets and exit of T cells to the periphery (26). The turnover of
immature CD4+CD8+ thymocytes is 3 to 4 days,
and that of mature thymocytes in the medulla is maximally 2 wk (35),
and some mature thymocytes take no more than 2 days to emigrate from
the thymus to the periphery (36). In agreement with these studies, we
found CD4+CD8- and
CD4-CD8+ single positive thymocytes in grafted
thymi 4 wk after transplantation (data not shown). Based on these
facts, it is reasonable to expect to observe first
ß2m+/+ thymus emigrants in the periphery 2 to
3 wk postgrafting. Given that thymus exports daily 1% of its cell
size (35), and that our grafts contained 10 to 40 x
106 cells 4 wk after grafting, 0.6 to 2.4 x
106 CD8+ cells (calculated as one-fifth of the
total thymus export) are estimated to be produced for 30 days. This is
well within the range of 2 x 106 CD8+ T
cells Takeda et al. found in the periphery 5 wk after they grafted MHC
class II-positive thymus into class II-deficient hosts (19). However, 2
or even 4 (data not shown) mo after grafting the
ß2m+/+ thymus, we were still unable to detect
any significant increase in peripheral CD8+ T cell
numbers.
There are two possibilities to explain the requirement for MHC class I.
The first possibility is that the CD8+ T cells generated in
the ß2m+/+ thymus never arrived in the
periphery because of a lack of additional signal that needs to be
delivered in the thymus by MHC class I-positive cells of nonepithelial
origin. This possibility is based on suggestions that positive
selection in the thymus may be a multistep process, requiring at least
two signals (37, 38). The second possibility is that mature
CD8+ T cells are able to emigrate despite the absence of
MHC class I-expressing bone marrow-derived cells in the thymus, but
that they need contact with MHC class I in the periphery. Functional
competence of CD8+ thymocytes (Fig. 3
) and reconstitution
of the CD8+ T cell compartment of grafted
ß2m-/- mice following injection of
allogeneic ß2m+/+ tumor cells (Fig. 5)
clearly argue in favor of the second hypothesis. In the absence of
peripheral MHC class I, however, these cells either failed to enter
their proper niche in the secondary lymphoid organs, or had a
drastically shorter life span.
Using a model analogous to the one presented in this work, it was
suggested recently that CD4+ cells may not require MHC
class II for immediate repopulation of periphery, but for long-term
survival (19). It is possible that these differences reflect
fundamentally different physiology of CD4+ and
CD8+ T cells. However, these findings may also be viewed as
essentially very similar: all naive T cells may need constant
subthreshold signaling for survival in periphery, but CD4+
cells may require these signals less frequently than CD8+
cells. Finally, different findings may be due to technical reasons.
Takeda et al. elected to graft total thymus, containing bone
marrow-derived cells, whereas we have first depleted donor thymus of
bone marrow-derived cells. MHC class II-positive cells (dendritic
cells, macrophages, and some B cells) were thus transferred into class
II-deficient recipients in experiments of Takeda and colleagues. These
passenger bone marrow-derived cells could have delivered the survival
signal in the thymic medulla. Alternatively, these cells could have
migrated to the periphery of graft recipients, and although in low
numbers, could have provided the signal(s) necessary for survival of
CD4+ recent thymic emigrants. Constant survival signaling
may be necessary for T cells, and as the transferred class II-positive
APCs faded with time due to turnover, CD4+ cells may have
lost the survival signal and their number declined in class
II-deficient recipients. Future experiments should determine whether
CD4+ and CD8+ thymic emigrants differ in the
requirements for peripheral repopulation. Interestingly, the finding
that CD8+ cells were found in significant numbers following
in vivo alloantigenic stimulation (Fig. 5) suggests that memory
CD8+ T cells may be relieved of the requirement for
periodic maintenance by self MHC class I and become long-lived. This is
in agreement with persisting memory CD8+ cells that are
found after adoptive transfer of immune lymphocytes to
ß2m-/- hosts (10, 34).
What kind of signaling events are induced by MHC class I? It has been
demonstrated that in nonstimulated thymocytes or lymph node T cells
taken ex vivo, a fraction of ZAP-70 is constitutively associated with
tyrosine-phosphorylated TCR 
-chain, but is not itself tyrosine
phosphorylated (39). These, or similar partial activation events may
reflect the type of interactions that mediate signals for T cells that
allow them to persist in the periphery. It is of interest to note that
TCR antagonist peptides induce different patterns of TCR -chain
phosphorylation without ZAP-70 recruitment or activation (40), and are
also capable of inducing positive selection in the thymus (41). Thus,
there is a distinct possibility that an interaction similar to the one
that induces positive selection in the thymus is also required for
peripheral maintenance of T cells, and that constant awareness of self
is required for survival of naive T cells before they are stimulated
with Ag.
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Acknowledgments |
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-
ugi,
Yang Liu, Jeanette Thorbecke, Yongrui Zou, and Juan Lafaille for
reading the manuscript. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. Stanislav Vukmanovi, Michael Heidelberger Division of Immunology, Department of Pathology, New York University Medical Center, 550 First Avenue, New York, NY 10016.
3 Abbreviation used in this paper: ß2m, ß2-microglobulin.
Received for publication August 28, 1997. Accepted for publication December 12, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/ß T cells in secondary lymphoid organs. J. Exp. Med. 177:891.ß T cell receptor cytotoxic T cells with major histocompatibility complex (MHC) class I antigen-directed cytotoxicity in ß2-microglobulin, MHC class I-deficient mice. Proc. Natl. Acad. Sci. USA 90:2837. in murine thymocytes and lymph node T cells. Immunity 1:675.[Medline]
and lack of Zap70 recruitment in APL-induced T cell clonal anergy. Cell 79:913.[Medline]
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