By
From the * Netherlands Cancer Institute, Division of Molecular Genetics, 1066 CX Amsterdam,
The Netherlands; Basel Institute for Immunology, 4005 Basel, Switzerland; and § Institute Necker,
INSERM 373, F-75730 Paris Cedex 15, France
In the thymus, T cells are selected according to their T cell receptor (TCR) specificity. After
positive selection, mature cells are exported from primary lymphoid organs to seed the secondary lymphoid tissue. An important question is whether survival of mature T cells is an intrinsic
property or requires continuous survival signals, i.e., engagement of the TCR by major histocompatibility complex (MHC) molecules in the periphery, perhaps in a similar way as occurring during thymic positive selection. To address this issue we used recombination-activating
gene (Rag)-deficient H-2b mice expressing a transgenic TCR restricted by I-Ed class II MHC
molecules. After engraftment with Rag/
H-2d fetal thymi, CD4+8
peripheral T cells
emerged. These cells were isolated and transferred into immunodeficient hosts of H-2b or H-2d
haplotype, some of the latter being common cytokine receptor
chain deficient to exclude rejection of H-2b donor cells by host natural killer cells. Our results show that in the absence, but
not in the presence, of selecting MHC molecules, peripheral mature T cells are short lived and
disappear within 7 wk, indicating that continuous contact of the TCR with selecting MHC
molecules is required for survival of T cells.
Positive selection of T cells in the thymus requires the
interaction of the TCR on immature thymocytes with
self-MHC molecules expressed on thymic epithelial cells
(1). This process is dependent on the continual interaction of TCRs to MHC molecules since the transfer of thymocytes exhibiting only the first signs of positive selection
(i.e., TCR upregulation and CD69 expression) into hosts lacking appropriate MHC molecule expression results in
the loss of the transferred cells (4, 5). The presence of certain intermediate stages of T cell development in different
gene-deficient mice also indicated that T cells were selected by a multistep process (6). Nevertheless, T cells do
acquire functional maturity within the thymus since they
can be stimulated to divide (9), as was found for recent
thymic emigrants (12).
After the export to secondary lymphoid organs, some
naive T cells do not divide but are long lived with an intermitotic lifespan of the order of 8 wk in euthymic mice, and
much longer in athymic mice (13, 14). These experiments
were performed in mice expressing the same MHC molecules in peripheral lymphoid tissue that induced positive selection in the thymus. Recently, some evidence was presented that MHC molecules in the peripheral lymphoid
organs may have a role in sustaining long-term survival of
mature T cells (15). We have addressed the same question
in a different experimental system and, even though we agree
that MHC molecules do support the survival of mature T
cells, we have obtained results that differ from those obtained
in the previous report (15). In our experiments, we have
grafted recombination activating gene (Rag)1-deficient mice
of H-2b haplotype that express a transgenic I-Ed-restricted
TCR with thymi from fetal H-2d Rag Mice.
BALB/c and BALB/c nu/nu mice were from IFFA-Credo (Orléans, France). BLACK nu/nu mice were from Bomholtgart (Ry, Denmark) and screened for H-2b homozygosity.
Rag-2- (18) and Rag-1- (19) deficient mice were H-2b homozygous. Hemagglutinin-specific TCR transgenic mice (ABII TCR)
on Rag-2 B Cell Depletion, Cell Sorting, and FACS Analysis.
Single cell
suspensions of thymus, lymph nodes, and/or spleen (RBCs lysed
or removed by Ficoll density gradient centrifugation) were prepared in PBS with 2% FCS. Where applicable, surface immunoglobulin-positive (sIg+) cells were depleted using Dynabeads (Milan, Switzerland).
/
mice. This allowed the positive selection of CD4+8
T cells expressing
the transgenic TCR. These cells were transferred into immunodeficient hosts of either H-2b or H-2d haplotype,
some of the latter being deficient in expression of the common cytokine receptor
chain (IL-2R
/
) and therefore devoid of NK cells (16, 17). The results show that H-2d-restricting MHC molecules are required for survival of the transferred T cells in secondary lymphoid tissue.
/
background have been described (8, 20). H-2d
Rag-2
/
mice were obtained from Drs. Antonius Rolink and
Shunichi Takeda (Basel Institute for Immunology, Basel, Switzerland; reference 15). These mice were crossed with IL-2R
/
mice to obtain H-2d Rag-2
/
IL-2R
/
mice. All breeding
was done in the animal colonies at the Basel Institute for Immunology (Basel, Switzerland) and at the Netherlands Cancer Institute (Amsterdam, The Netherlands).
d; reference 21) mAbs were labeled with FLUOS (Boehringer Mannheim, Mannheim, Germany). Heat stable antigen (HSA)-specific
mAbs M1/69 (22) were biotinylated. FITC-labeled 104.2.1 mAbs
(anti-Ly-5b; reference 23) were a gift of Dr. Hans-Reimer Rodewald (Basel Institute for Immunology, Basel, Switzerland). Anti-CD4-PE, anti-CD8-Red613 (GIBCO BRL, Gaithersburg, MD),
and streptavidin-allophycocyanin (Molecular Probes Inc., Eugene, OR) conjugates were obtained commercially.
Lymphocyte Proliferation Assay.
Cell sorter purified responder
cells were cultured with 5 × 105 X-irradiated (2,200 rad) stimulator cells in 200 µl Iscove's modified Dulbecco's medium supplemented with FCS (10%), -mercaptoethanol (5 × 10
5 M), penicillin (100 IU/ml), and streptomycin (100 mg/ml). To some
cultures, peptide 107-119 of influenza hemagglutinin (SVSSFERFEIFPK) was added at a final concentration of 5 µM. Cultures were kept in a water-saturated atmosphere of 6% CO2 in air
at 37°C. After 48-60 h, 1 µCi [3H]thymidine (Amersham Corp.,
Arlington Heights, IL) was added and cells were cultured for a
further 12-24 h when they were harvested. Incorporated radioactivity was measured by standard liquid scintillation counting.
Fetal Thymus Transplantation and Adoptive Transfers.
Fetal H-2d
Rag-2/
thymi were isolated at days 14-16 of gestation (plug
day = day 0). For some experiments (Fig. 1), thymus lobes were
isolated from BALB/c mice and cultured 5 d in medium containing 1.35 mM 2
-deoxyguanosine (dGuo; Sigma Chemical Co.,
St. Louis, MO). 1-2 lobes were transplanted under the kidney
capsule of H-2b or H-2b/d ABII TCR Rag-2
/
mice. 6-16 wk
later, cells were isolated from lymph nodes and spleen, stained
with CD4, CD8, and I-A
d-specific mAbs, and cell sorter purified. CD4+8
I-A
d
and CD4
8low/+I-A
d
cells were injected
intravenously into various 4-6-wk-old recipient mice.
H-2d-restricted CD4+8 T Cells in Thymus Grafted ABII TCR
Rag
/
H-2b Mice.
In our studies, we used ABII TCR
transgenic mice that express a transgenic TCR specific for
peptide 111-119 of influenza hemagglutinin presented by
I-Ed class II MHC molecules. These mice were crossed
onto the Rag
/
background to exclude the interference
of TCRs with unknown specificity due to lack of allelic
exclusion of the TCR-
locus (25, 26). To obtain T cells
that are selected in the thymus but not able to encounter
the selecting MHC molecules in peripheral lymphoid tissue, we transplanted H-2b ABII TCR Rag
/
mice with
fetal thymi of H-2d haplotype that had been depleted of
hematopoietic cells or were from Rag
/
background. (It
is possible that some donor thymus-derived I-Ed-expressing cells emigrate from the graft. This will be addressed below.) Under such conditions, the thymus graft is seeded by
T cell precursors of the host such that mature CD4+8
T
cells with the transgenic TCR develop in the grafted H-2d,
but not the host H-2b thymus (Fig. 1). Subsequently,
CD4+8
T cells from the grafted thymus are exported to
the periphery (Fig. 2). Such CD4+8
peripheral T cells are
not present in H-2b ABII TCR Rag
/
mice, since cells
with the I-Ed-restricted ABII TCR cannot develop in a H-2b
thymus (8). There are also CD4
8low T cells in these mice
that will be discussed below.
To confirm that the CD4+8
CD4+8 Peripheral T Cells from H-2d Thymus-Grafted H-2b
ABII TCR Rag
/
Mice Disappear in H-2b but Not in H-2d Adoptive
Hosts.
We have shown previously that CD4
8low cells
with the transgenic ABII TCR are an abundant subset in
peripheral lymphoid organs of H-2b ABII TCR Rag
/
mice and therefore do not need I-Ed MHC molecules for
selection and survival (8). This population most likely results from the unusual early expression of the
/
-TCR in
TCR transgenic mice leading to the formation of
/
lineage T cells that express the transgenic
/
-TCR on the
cell surface as discussed by Bruno et al. (27). Here, this subset serves as a convenient internal control to determine engraftment.
In other experiments, we have followed the fate of CD4+8
Our data show that appropriate MHC molecules are required to support the survival of mature /
T cells in peripheral lymphoid tissue; a conclusion in line with previously published experiments (15). In the latter study,
however, polyclonal CD4+8
T cells in thymus-grafted Rag
class II MHC double deficient mice appeared to survive
much longer since significant numbers of cells could still be
found 16 wk after export from the thymus ceased. This
may be due to the fact that in these experiments, CD4+8
T cells with class I MHC-restricted TCRs (36) could
interact with class I MHC molecules expressed in the peripheral lymphoid tissue or due to the fact that some class II
MHC-positive cells had migrated from the transplanted
thymus into the periphery. In both of these cases, T cells
could have been stimulated by antigen. The high proportion of proliferating CD4+8
T cells at various points in
time after thymus transfer could indicate that this was indeed the case, and some CD4+8
T cells might have rather
disappeared because of exhaustion (39, 40). These possibilities were excluded in our experiments; the CD4+8
T
cells were of known antigen specificity and MHC restriction. Any potential class II MHC molecule-expressing cells
originating from the thymus graft were removed by cell
sorting before transfer into adoptive recipients.
In line with our previous observations, we noticed expansion of CD4+8 ABII TCR-expressing cells in H-2d
mice (reference 41 and this report). Currently, it is not
clear whether T cell survival in the absence (13, 14) or the
presence (41) of proliferation (or both possibilities) reflects
the normal physiologic situation. Interestingly, normal
mice that had been thymectomized have some cells of naive phenotype that label with BrdU (42).
Irrespective of the MHC environment, CD48low cells
that are not dependent on positive selection in the thymus,
did expand after transfer. Presently, the biology of these
cells is not well understood and it has been speculated that
these cells represent
/
lineage T cells expressing the
transgenic
/
-TCR (27).
While it becomes established that T cells require the interaction of their TCRs with selecting MHC molecules for
survival in the peripheral lymphoid tissue, the mechanism
behind this requirement is unknown. In the thymus, immature CD4+8 cells express low levels of the cell death-
repressing bcl-2 protein. They have a half life of 3 d (43)
unless their TCR binds with sufficient affinity to self-MHC molecules resulting in maturation that is accompanied by bcl-2 upregulation (44). One might then speculate that the level of bcl-2 expression and, hence, survival
is (indirectly) regulated by TCR ligation with selecting MHC
molecules in the absence of antigen. In that respect, peripheral survival could be similar to thymic positive selection. The
data reported on T cells from bcl-2-deficient mice are compatible with such a hypothesis (48). We have investigated
bcl-2 expression by intracellular staining of CD4+8
cells
from thymus-grafted H-2b ABII TCR Rag
/
and H-2d
ABII TCR Rag
/
mice. However, the differences we observed were far less dramatic than during thymic positive
selection (mean fluorescence reduced to 74 compared to 98 in controls, whereas in the thymus, a threefold difference was
detectable: 44 versus 120 in an independent experiment). This could be due to the fact that cells with low bcl-2 expression are rapidly dying and eliminated and escape detection.
Further, it will be of interest to determine whether TCR
contact with selecting MHC molecules on any type of cell
is sufficient for T cell survival or whether the selecting
MHC molecules have to be encountered on a specific cell
type. The latter would be analogous to the requirement of
TCR-MHC molecule interaction on thymic epithelial
cells for thymic positive selection (3). Interestingly, RelB-deficient mice that lack dendritic cells have an increased proportion of activated T cells, whereas absolute numbers of T
cells are reduced (52, 53). The former might be due to limited self-censorship in the thymus followed by peripheral activation by self-antigens the T cells were not tolerized for in the thymus (52). The latter, however, could indicate
that (naive) peripheral T cell survival requires TCR interaction with selecting MHC molecules on dendritic cells.
The data of DeKoning et al. on transfer of naive TCR
transgenic T cells into RelB/
mice support this theory (53).
Address correspondence to Jörg Kirberg, Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, NL-1066 CX Amsterdam, The Netherlands. Phone: 0031-20-512 19 98; FAX: 0031-20-512 20 11; E-mail: kirberg{at}nki.nl
Received for publication 2 May 1997 and in revised form 30 July 1997.
1 Abbreviations used in this paper: dGuo, 2We thank M. Dessing, S. Meyer, and E. Noteboom for expert help with flow cytometry and cell sorting; the
animal care takers (especially E. Wagner and W. Metzger, and L. Tolkamp in Basel, Switzerland and Amsterdam, The Netherlands, respectively) for making possible these experiments; H.-P. Stahlberger for art
work; P. Krimpenfort for providing the IL-2R/
mice; and John D. Allen, Thomas Brocker, and Hergen
Spits for reading the manuscript. The TCR clonotype specific mAb 6.5 was produced by B. Riwar and H. Kishi. The Basel Institute for Immunology was founded and is supported by F. Hoffmann-La Roche Ltd.
(Basel, Switzerland). J. Kirberg receives a fellowship from the Boehringer Ingelheim Foundation (Stuttgart,
Germany).
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