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* Institut National de la Santé et de la Recherche Médicale, Unité 345, and
Laboratoire d’Expérimentation Animale et de Transgénèse, Faculté de Médecine Necker-Enfants Malades, Université René Descartes, Paris, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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-deficient mice, and irradiated normal mice.
In all three recipients, the absolute number of recovered cells was
much smaller than in normal mice. In addition, transferred naive T
cells acquired a memory-like phenotype that remained stable with time.
Finally, injected cells were rapidly replaced by host thymic migrants
in irradiated normal mice. Only continuous output of naive T cells by
the thymus can generate a full compartment of truly naive T cells.
Thus, conversion of naive T cells to a memory-like phenotype in
lymphopenic hosts is not related to a homeostatic mechanism that fills
the peripheral naive T cell pool. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Recent studies have followed the phenotypic and functional
characteristics of naive T cells over a relatively long period (>1 mo)
(14, 15, 16, 17, 21). They all showed that, during proliferation,
naive T cells converted to a memory T lymphocyte phenotype. In all but
one case, the phenotypic and functional characteristics of transferred
T cells remained stable over time. Indeed, only Goldrath et al.
(14), using irradiated normal mice rather than
recombination-activating gene
(rag)3-deficient mice
as lymphopenic recipients, observed that the transferred cells stopped
cycling and reverted to a naive phenotype after filling the
peripheral T cell pool. Moreover, they showed that the same monoclonal
naive T cells continued to divide in rag-deficient mice, in which the
lymphocyte compartment was never reconstituted. Thus, they proposed
that, in rag-deficient hosts, the absence of fully developed secondary
lymphoid organs or the absence of B cells might explain the
discrepancies between their data and results published by other groups
(15, 16). Our recent results showing that homeostasis is
not restored in CD3-deficient mice rule out both hypotheses
(21).
In this study, to directly examine whether a limited number of naive T
cells transferred to a lymphopenic host can truly fill the peripheral
naive T cell pool, we compared the expansion and phenotype of naive T
cells transferred to rag-deficient mice, CD3-deficient mice, and
irradiated normal mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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H-2b/b AND TCR-transgenic
rag-20/0 mice (21),
H-2k/k AND TCR-transgenic
rag-20/0 mice (21),
H-2k/k CD3-deficient mice (21),
B10.A 5CC7 TCR-transgenic rag-20/0 mice
(22), B10.A CD3-deficient mice (22), and
B10.A mice were maintained in our animal facilities. B10BR mice,
C57BL/6 mice, C57BL/6 Ba (Thy1.1) mice, H-2b/b
CD3-deficient mice, and C57BL/6 rag-20/0 mice
were obtained from Centre de Développement des Techniques
Avancées pour l’ Expérimentation Animale (Orléans,
France).
Adoptive transfer of naive T cells
One million CD4+ T cells from lymph nodes
or spleen of AND TCR-transgenic rag-20/0 mice
were injected i.v. into rag-20/0 mice,
CD3-deficient mice, and irradiated normal mice of the same
haplotype. Spleens and lymph nodes were recovered and pooled at various
times after transfer.
Three million CD4+ T cells from lymph nodes of
B10.A 5CC7 TCR-transgenic rag-20/0 mice were
injected i.v. into B10.A CD3-deficient mice and irradiated B10.A
mice. Spleens and lymph nodes were recovered and pooled 14 days after
transfer.
Normal mice were sublethally irradiated (650 rad) 2 days before transfer.
Flow cytometry
Abs were purchased from BD PharMingen (San Diego, CA). The
following Ab combinations were used: PE-conjugated anti-CD8,
FITC-conjugated anti-V
11, PerCP-conjugated anti-CD4, and
biotinylated anti-V
3 revealed by allophycocyanin streptavidin
(BD PharMingen); PE-conjugated anti-V11,
FITC-conjugated anti-V3, PerCP-conjugated anti-CD4, and
biotinylated anti-CD25 or CD44 revealed by allophycocyanin
streptavidin; PE-conjugated anti-Thy1.2, FITC-conjugated
anti-CD8, PerCP-conjugated anti-CD4, and biotinylated
anti-V3 revealed by allophycocyanin streptavidin; PE-conjugated
anti-Thy1.2, FITC-conjugated anti-V11, PerCP-conjugated
anti-CD4, and biotinylated anti-CD25 or CD44, revealed by
allophycocyanin streptavidin; PE-conjugated anti-lineage (Lin)
markers (Lin = CD19 + GR.1 + MAC.1 + TER119 + NK1.1),
FITC-conjugated anti-CD45, PerCP-conjugated anti-CD4, and
biotinylated anti-V3 revealed by allophycocyanin
streptavidin.
Calculations
Absolute numbers of recovered CD4+ T cells and
recovered V3+V11+CD4+
T cells were calculated at various times after transfer of
AND CD4+ T cells to irradiated C57BL/6 and B10BR mice. In
normal C57BL/6 and B10BR mice, some CD4+ T cells coexpress
a TCR V11 chain and a TCR V3 chain (C57BL/6: p =
0.24%; B10BR: p = 0.55%). To precisely estimate the
number of donor (AND)-derived CD4+ T cells among all
recovered V3+V11+CD4+ T
cells, the following calculations were performed:
(V3+V11+CD4+)recovered
=
(V3+V11+CD4+)host
+
(V3+V11+CD4+)AND.
(CD4+)recovered =
(CD4+)host +
(V3+V11+CD4+)AND,
all AND CD4+ T cells coexpressing a V11 chain and a
V3 chain.
Moreover,
(V3+V11+CD4+)host
= P x (CD4+)host,
where P represents the proportion of host-derived
CD4+ T cells coexpressing a V11 chain and a V3 chain.
Therefore,
(V3+V11+CD4+)AND
=
(V3+V11+CD4+)recovered
- P x (CD4+)host,
and
(V3+V11+CD4+)AND
=
((V3+V11+CD4+)recovered
- P x (CD4+)recovered)/(1 -
P).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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One million lymph node CD4+ T cells from AND
TCR-transgenic rag-20/0 mice
(H-2b/b or H-2k/k) were
transferred to rag-2-deficient mice, CD3-deficient mice, and
irradiated normal mice of the same MHC haplotype.
As previously shown (21), no significant expansion of
injected AND CD4+ T cells was found when
H-2b/b AND CD4+ T cells were
transferred to H-2b/b CD3-deficient mice (Fig. 1
A): the absolute numbers of
recovered AND CD4+ T cells remained low, but constant.
Similar results were found after transfer to rag-2-deficient mice,
except that cell recovery was 3-fold lower than in
CD3-deficient mice.
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3+V11+CD4+ T
lymphocytes was intermediate between values obtained in rag-deficient
mice and CD3-deficient mice, and this number fell strongly with time
thereafter (Fig. 1
A). The absolute numbers of host and
AND-derived V3+V11+CD4+ T
cells among all recovered
V3+V11+CD4+ T cells were
estimated in these chimeras (see Materials and Methods)
(Fig. 1B). Calculation showed that virtually no injected AND
CD4+ T cells could be recovered 12 wk after transfer to
irradiated normal mice. Indeed, all
V3+V11+CD4+ T cells were of
host origin 12 wk posttransfer. These data were further confirmed by
transferring AND CD4+ T cells (Thy1.2) to congenic
irradiated C57BL/6 Ba mice (Thy1.1) (see Fig. 3). Expression of
activation markers (CD25, CD44) by AND CD4+ T cells was
studied 2 wk after transfer, at which time nearly all
V3+V11+CD4+ T cells were
derived from injected AND CD4+ T cells in irradiated normal
mice (Fig. 1B). CD25 and CD44 expression was strongly
up-regulated after transfer to rag- and CD3-deficient mice (Fig. 1C). No CD25 expression and slight up-regulation of CD44
expression by V3+V11+CD4+ T
cells were observed after transfer to irradiated C57BL/6 mice,
suggesting that injected AND CD4+ T cells had undergone
less marked activation than in the other two recipients.
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-deficient mice
(21) (Fig. 1). We thus performed similar experiments with
H-2k/k AND CD4+ T cells, as we have
previously shown that these cells expand strongly when transferred to
H-2k/k CD3-deficient mice (Ref.
21 and Fig. 2A).
Surprisingly, these cells did not expand when transferred to irradiated
B10BR mice (Fig. 2A). By estimating the numbers of AND
CD4+ T cells in these transfers, we found that, as after
transfer of H-2b/b AND CD4+ T cells,
H-2k/k AND CD4+ T cells disappeared
after transfer to irradiated mice (Fig. 2B). Similarly, 1 wk
after transfer, CD44 up-regulation on H-2k/k AND
CD4+ T cells was less marked in irradiated mice than in
CD3-deficient mice (Fig. 2C). Together with the observed
lack of expansion, this suggested that naive AND CD4+ T
cells were submitted to a far less marked activation phase in
irradiated mice than in CD3-deficient mice. Therefore, the
activation and subsequent expansion of injected naive T cells seemed to
be inversely proportional to the absolute number of preexisting T cells
in the host.
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-deficient
mice they proliferated, resulting in their expansion and conversion to
a memory-like phenotype that remained stable with time
(22), whereas they did not expand or convert to a
memory-like phenotype after transfer to irradiated normal B10.A mice
(Table I). Therefore, independently of
the hosts used, activation of naive CD4+ T cells did not
lead to filling of the peripheral naive T cell pool. Furthermore,
absolute numbers of recovered injected cells fell rapidly after
transfer to irradiated normal mice, probably reflecting competition for
space between injected T cells and newly produced host T cells
(23, 24, 25). Contrary to Goldrath et al. (14),
we did not find that naive T cells expanded better in irradiated mice
than in T cell-deficient recipients (rag-deficient or CD3-deficient
mice). One major methodological difference was that we injected lymph
node naive T cells instead of a pool of spleen and lymph node cells
(14).
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One million lymph node or spleen CD4+ T cells from
H-2b/b AND TCR-transgenic
rag-20/0 mice (Thy1.2) were transferred to
irradiated normal C57BL/6 Ba mice (Thy1.1). For 2 wk after transfer,
recovery of AND CD4+ T cells
(Thy1.2+V3+CD4+ cells) was
similar with spleen and lymph node cells (Fig. 3, A and B).
Moreover, AND CD4+ T cells converted to a memory phenotype
in both cases (data not shown). Four weeks after spleen cell transfer,
the absolute number of recovered AND CD4+ T cells started
to increase, reaching a plateau at 8 wk, whereas, as shown above (Fig. 1), the absolute number of AND CD4+ T cells in mice
injected with lymph node cells fell rapidly (Fig. 3, A and
B). Moreover, 8 wk after transfer, AND CD4+ T
cells recovered after spleen cell injection exhibited a true naive
phenotype, which contrasted with the stable memory-like phenotype of
AND CD4+ T cells recovered after lymph node cell injection
(Fig. 3C).
It is unlikely that intrinsic differences between lymph node- and
spleen-derived naive T cells would affect their behavior after transfer
to irradiated animals to such an extent. A more logical explanation
would be that the hematopoietic precursors contained in the spleen of
adult mice (26, 27) reconstituted the thymuses of
irradiated hosts, thereby permitting the generation of large numbers of
naive AND CD4+ T cells. Indeed, 15-fold more hematopoietic
precursors (defined by the absence of expression of Lin markers and the
expression of CD45) are coinjected together with 1 x
106 spleen AND CD4+ T cells than with
1 x 106 lymph node AND CD4+ T
cells (Fig. 4).
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At various times after transfer of lymph node or spleen AND
CD4+ T cells to irradiated normal mice, thymocytes were
recovered, counted, and stained for CD4, CD8, Thy1.2, and V3 surface
expression. As observed in the periphery of these mice (see above), no
difference between spleen and lymph node cell transfer was noted for 2
wk after transfer: at these early time points the thymus was
reconstituted only by host-derived precursors (Fig. 5, A and B). Later
after spleen cell transfer, but not after lymph node cell transfer,
thymocytes comprised large numbers of donor cells. These results could
not be explained by reentry of activated peripheral T cells into the
thymus, as all thymic subsets comprised donor-derived cells (Fig. 5, A and B). Indeed, 4 wk after transfer and
onwards, a large proportion of immature double-positive thymocytes were
found to derive from injected splenocytes (Fig. 5B). By
contrast, no immature double-positive thymocytes were found to derive
from injected lymph node cells at any time point studied. Most mature
CD4+ thymocytes produced 4 wk after spleen cell transfer
were AND CD4+ T cells, and this production was stable with
time (Fig. 5A). These results suggested that the
hematopoietic precursors injected together with spleen AND
CD4+ T cells possessed self-renewal capacities. Thus, our
results confirm that spleen cell transfer to irradiated animals permits
thymus reconstitution by donor cells (26, 27).
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Finally, to explain the different behavior of spleen naive T cells in
rag-deficient recipients and irradiated normal hosts (14),
we transferred one million lymph node or spleen CD4+ T
cells from H-2b/b AND TCR-transgenic
rag-20/0 mice to irradiated or nonirradiated
CD3-deficient mice. Thymus reconstitution by donor cells was studied
8 wk after transfer (Fig. 5C). Our results clearly show that
both irradiation and subsequent injection of spleen cells are required
for host thymus reconstitution by donor cells, in agreement with early
papers describing thymic reconstitution after irradiation and injection
of hematopoietic precursors (28, 29, 30, 31, 32). Thus, these
observations, together with the finding that cell recovery was much
lower in rag-2-deficient mice than in CD3-deficient mice (Fig. 1),
provide a highly plausible explanation for the different behavior of
spleen naive T cells after transfer to rag-deficient recipients and
irradiated hosts.
Naive T cells transferred to lymphopenic recipients (rag-deficient
mice, CD3-deficient mice, and irradiated normal mice) failed to fill
the peripheral naive T cell pool (15, 16, 17, 21). Indeed,
absolute numbers of recovered T cells were far below those in the full
peripheral naive T cell pool of normal mice. Moreover, injected naive T
cells acquired a memory-like phenotype that remained stable with time,
despite the absence of foreign antigenic stimulation, and their
functional capacities were modified, enhanced, or abolished
(15, 16, 17, 21). Finally, injected cells were rapidly
replaced by host thymic migrants after transfer to irradiated normal
mice. These data argue against the view that the proliferation of naive
T cells in lymphopenic mice represents a homeostatic mechanism
regenerating the naive T cell pool. Further studies should focus on the
mechanisms underlying this proliferation and the relevance of this
process to disease-induced lymphopenia.
Note. During the processing of this manuscript, an article on the same field reaching similar conclusions was published (33).
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Bruno Lucas, Institut National de la Santé et de la Recherche Médicale, Unité 345, Faculté de Médecine Necker-Enfants Malades, 156 rue de Vaugirard, F-75730 Paris Cedex 15, France. E-mail address: lucasb{at}necker.fr
3 Abbreviations used in this paper: rag, recombination-activating gene; Lin, lineage.
Received for publication January 11, 2002. Accepted for publication March 18, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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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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) and estimated numbers of host (X) and AND (
)
V
) and
Thy1.2+V