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TCR Transgenic Mice. II. Competitive Fitness of Dual TCR CD8+ T Lymphocytes in the Peripheral Pools1
Lymphocyte Population Biology Unit, Unité de Recherche Associée, Centre National de la Recherche Scientifique, Institut Pasteur, Paris, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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TCR
transgenes, both restricted to the MHC H-2Db class I
molecule. We have previously shown that, in these DTg mice, most
peripheral CD8 T cells express one TCR chain associated with two
TCR chains, as in one-third of the mature T cells from normal mice.
We examined the functional behavior of the dual-receptor CD8 T cells
developing either in the absence or in the presence of self-Ag. The
dual-receptor CD8 T cells, which develop in absence of self-Ag, show
efficient responses to immunization and remain sensitive to induction
of peripheral tolerance. In contrast to single TCR T cells, the
dual-TCR cells, when tolerized upon exposure to high levels of self-Ag,
are not deleted and therefore may exert important regulatory functions.
When developing in the presence of self-Ag, the
dual-receptor-expressing CD8 T cells escape central deletion, but are
not fully competent to respond to cognate stimuli. Overall, we found
that the dual-TCR CD8 T cells show a poor competitive value and can be
out-competed by single-TCR cells, both in the course of immune
responses and in reconstitution experiments. The decreased fitness of
the dual-receptor cells may contribute to diminishing the autoimmune
hazard that they could represent. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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chain is never fail
proof and 
1% of the mature T cells contain two productive
TCR alleles (1, 2). Second, it is because TCR chain
rearrangements proceed simultaneously in both chromosomes (3, 4) and 30% of the human T cells (5) and
a fraction of the mouse T cells (6, 7) express two
TCR chains (4, 5, 6). Potentially these dual-receptor T
cells could play an important role in autoimmunity. The presence of a
second TCR would allow cells bearing a self-reactive TCR to bypass
negative selection in the thymus, in virtue of its lower expression. At
the periphery, these T cells once activated by a non-self Ag would
acquire a lower threshold of activation, respond to self-peptide/MHC,
and cause disease. Several in vivo experimental models have examined
this possibility. Studies on mice hemizygous for the TCR locus do
not seem to support the role of dual-TCR-expressing T cells to
develop autoimmune diseases, i.e., diabetes in nonobese diabetic mice
(8). However, in transgenic
(Tg)3 mouse models,
co-expression of two TCRs has been shown to rescue self-reactive T
cells from tolerance induction, allowing their exit into the peripheral
pools (9, 10). These self-reactive T cells could be
stimulated in vitro to anti-self effector functions via the second
receptor (9), and their in vivo presence was correlated to
the induction of autoimmune diabetes when the relevant Ag was expressed
by the target tissue (10). The role of dual-receptor T cells in autoimmune diseases, however, is strictly dependent on their ability to be positively selected in the thymus, to survive, and to remain fully reactive in the peripheral pools. Both thymus positive selection (11) and peripheral T cell survival require receptor engagement by MHC molecules (12, 13, 14, 15, 16). The presence of two receptors with different specificity imposes some constraints on the selection, survival, and functional abilities of dual-receptor T cells. Indeed, it was recently shown that the decreased surface density of specific receptors reduces the thymus positive selection of dual-receptor T cells (17). Moreover, the functional capacity of peripheral dual-receptor T cells has also been challenged because expression of two TCRs does not always confer reactivity to two unrelated Ags (18).
We have derived a line of Rag2-deficient mice bearing two complete
rearranged TCR transgenes, one specific for the HY male Ag
(15, 19) and the second specific for the gp33-41 peptide
of lymphocytic choriomeningitis virus (LCMV) (20). Both
receptors are restricted to the same MHC H-2Db
class I molecule. We have examined the thymus selection of the CD8 T
cells in these double transgenic (DTg) mice in the absence or in the
presence of the HY male self-Ag (35). In female DTg mice, most mature
peripheral CD8 T cells express only the TCR chain from the aHY
transgene associated with the two TCR chain transgenes. In male
mice, the presence of a second TCR chain allows a significant number
of CD8 T expressing a self-reactive receptor to escape central deletion
and migrate to the peripheral pools. Thus, in both cases, most of the
CD8 T cells from the DTg mice express one TCR associated with two
TCR chains, like 30% of the peripheral T cells from a normal
mouse. Therefore, these DTg mice provide a unique model for studying
the functional behavior of dual-TCR CD8 T cells. In the present
investigation, we compared the capacity of single- and dual-receptor
CD8 T cells to colonize and repopulate peripheral pools, as well as to
respond to antigenic stimulation in vivo.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 mice Tg for the anti-HY TCR (VT3.70.V8.2)
(15, 19) or the P14 TCR (V2.V8.1) (20)
were crossed into a Rag2-deficient background. The mice obtained (MoaHY
and MoP14) were intercrossed to give rise to MoaHY.MoP14 DTg mice. All
of these strains were maintained in specific pathogen-free isolators at
the Centre de Développement des Techniques Avancées pour
l’expérimentation Animale-Centre National de la Recherche
Scientifique (Orléans, France).
B6.Rag2-/- mice (21) and
B6.CD3
-/- mice (22) were from
the Centre de Développement des Techniques Avancées pour
l’expérimentation Animale-Centre National de la Recherche
Scientifique, and C57BL/6 mice were from IFFA-CREDO
(Saint-Germain-sur-l’Arbresle, France).
Flow cytometry
The following mAbs were used: anti-CD8 (53-6.7),
anti-V2 (B20.1), anti-V8.1/2 (MR5-2), anti-Thy1.1
(OX-7), anti-Thy1.2 (30-H12), anti-CD3 (145-2C11),
anti-CD4 (L3T4/RM4-5), anti-CD69 (H1.2F3), anti-CD25
(PC61), and anti-CD24/HSA (M1/69) from BD PharMingen (San Diego,
CA) and anti-CD44 (IM781) and anti-CD62L (MEL14) from Caltag
Laboratories (San Francisco, CA). The anti-VT3.70 and the F23.2
anti-V8.2 were from B. Rocha (Institut National de la
Santé et de la Recherche Médicale Unité 345, Institut
Necker, Paris, France). Cell-surface staining was performed with
the appropriate combinations of FITC, PE, TRI-Color (Caltag
Laboratories), PerCP (BD Biosciences, San Jose, CA), Biotin, and
APC-coupled Abs. Biotin-coupled Abs were revealed by APC-, TRI-Color-,
or PerCP-coupled streptavidin. Dead cells were excluded by
light-scattering gating. All analyses were performed with a FACScalibur
(BD Biosciences) interfaced to Macintosh CellQuest software (Apple
Computer, Cupertino, CA).
Bone marrow (BM) chimeras and peripheral T cell transfers
Host Rag2-/-B6 mice were lethally
irradiated (900 rad) in a 137Ce source and
injected i.v. with 2–4.106 BM cells. This
inoculum contained BM cells from different donors, mixed at several
ratios (23). Nonirradiated female or male
B6.CD3-/- hosts were also injected i.v. with
CD8 LN T cell populations. By using mice differing by Thy1 or Ly5
allotype and Tg TCR chains, we were able to discriminate the cells that
originated from the different donor and host mice. Spleen, inguinal,
and mesenteric lymph node (LN) cell suspensions were prepared, and the
number and phenotype of the cells from each donor population were
evaluated. The total peripheral T cell numbers shown in
Results represent the number of cells recovered in the
host’s spleen added to twice the number of cells recovered from the
host’s inguinal and mesenteric LNs.
In vitro proliferation assays
Spleen cells from Tg mice were incubated in 96-well plates (105 cells/well) at 37°C, 5% CO2, in a final volume of 200 µl in complete RPMI 1640 medium supplemented with 10% FCS (Boehringer Mannheim, Mannheim, Germany). Cells were stimulated with Con A (Sigma-Aldrich, St. Louis, MO), anti-CD3 (BD PharMingen), or the Tg TCR specific peptides gp33-41 (24) (KAVYNFATM) and Smcy-3 peptides (25) (KCSRNRQYL) purchased from Neosystem (Strasbourg, France) and used with a >95% purity. After 1–4 days of culture, cells were pulsed overnight with 0.5 µCi [3H]thymidine (ICN Pharmaceuticals, Costa Mesa, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TCR DTg Rag2-deficient mice
By crossing two different lines of TCR Tg
B6.Rag2-/- mice, we obtained MoaHY.MoP14 (DTg)
mice bearing two MHC H-2Db class I-restricted TCR
transgenes. One receptor, aHY, is specific for the HY male Ag
(V8.2+VT3.70+) and
the second, P14, is specific for the gp33-41 peptide of the LCMV
(V8.1+V2+). In these
DTg mice, due to the absence of Rag2, lymphocytes can only express
chains from the two rearranged TCR transgenes (21).
Lymphocyte development in the thymus only gives rise to
CD4-CD8+ single positive
(SP) cells, indicating that the random association between the - and
the -chains from the two transgenes does not allow positive
selection by MHC class II. Studies on the reconstitution of
CD3-/-H-2Db-/- chimeras
reconstituted with BM cells from DTg donors have shown that, in the DTg
mice, >99% of the CD8 cells are restricted to the MHC
H-2Db class I molecule (35).
In female DTg mice, we have found that 99% of the peripheral CD8 T
cells express only the TCR V8.2+ chain from
the aHY transgene (35). Less than 1% of the total CD8 T cells are
V8+8.2-V2+T3.70-.
In contrast, the majority (80%) of the peripheral CD8 T cells (Fig. 1
A) express the two TCR
chains. These V2+T3.70+
CD8 T cells have a naive phenotype, in that they are
CD44-, CD62Lhigh,
CD25-, and CD69- (data
not shown). About 20% of the CD8 T cells express a single TCR
chain; i.e., they are either
V2+T3.70- (5–15%)
or V2-T3.70+
(5–15%) (Fig. 1A). Whereas both DTg and
V2-T3.70+ single cells
are CD44-, the single
V2+ cells are CD44int,
as in the MoP14 mice (Fig. 1B). In conclusion, in the
peripheral pools of female DTg mice, most CD8 cells are
V8.2+V2+T3.70+;
i.e., they express one TCR chain and two different TCR chains,
like 30% of the T cells from a normal mouse (5, 6).
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Because the majority of the cells express two TCR chains, CD8 T
cells from DTg mice represent an ideal model to study the physiological
behavior of one-third of the T cells from normal mice. We first
addressed the question of whether the expression of two TCR transgenes
could hinder the selection and survival fitness of the CD8 T cells. We
compared the development and accumulation of single and DTg CD8 T cells
in the same Rag2-/- hosts reconstituted with BM
precursors from MoP14, MoaHY, or MoaHY.MoP14 DTg donors either
injected alone or mixed at different ratios (23). Two
months later, the female chimeras co-injected with BM cells from MoP14,
MoaHY, and DTg donors showed a hierarchy of T cell selection and
accumulation in which MoP14 > MoaHY = DTg CD8 T cells (Fig. 2). Thus, in the chimeras co-injected
with a 10:90 cell ratio of BM cells from MoP14 (Thy1.2) and MoaHY
(Thy1.1) donors, >60% of the mature T cells were from P14 origin
(Fig. 2A). In the chimeras injected with a 50:50 ratio of
MoP14 and DTg cells, there was also a preferential selection of the P14
CD8 T cells, which occupy 80–90% of the peripheral T cell pool
(Fig. 2B). In these later chimeras, populations of single
TCR-expressing cells of DTg BM origin were rare or absent. In the
chimeras reconstituted with a mixture of MoaHY (Thy1.1) and DTg
(Thy1.2) BM, the cells from DTg origin (Thy1.2) represent the majority
(75–80%) of the thymus double negative (DN) precursors. Among the
mature thymus SP and peripheral populations, however, cells expressing
two TCR chains account for 50% of the cells from DTg origin, less
than the 80% present either in the original DTg mice (Fig. 1
) or in
the control chimeras reconstituted with 100% BM from DTg donors (data
not shown). This is due to a significant increase in the fraction of
single VT3.70-V2+ in
the peripheral pools. These results suggest that, among the CD8 T cells
from DTg origin, those cells expressing the TCRVT3.70 chain are
competitively less fit to populate the peripheral T cell pools than
those expressing the TCRV2 chain alone.
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We next compared the in vivo immune responses and the
proliferation of mature CD8 T cells from MoP14, MoaHY female, and DTg
female mice transferred into T cell-deficient
CD3-/- adoptive hosts (Fig. 3). In absence of Ag, in female hosts,
CD8 T cells from MoaHY or DTg female donors persist at similar numbers
from days 1–15 after transfer (Fig. 3A). In contrast, the
number of cells from MoP14 donors augments to a plateau of 1–2 x
106 cells at day 14. This increase nevertheless
was 10-fold lower than that observed for transferred polyclonal
CD8 T cell populations (data not shown).
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B). The kinetics of response and the long-term persistence
differed between the dual and the single V-expressing CD8 T cell
populations from DTg donors (Fig. 3C). The number of cells
expressing single
V2-T3.70+ and dual
V2+T3.70+ increased to
similar numbers (Fig. 3C). The expansion of the
V2-T3.70+ cells
continued slightly longer (Fig. 3, B and C) to
reach a peak at day 7, but when in the presence of other CD8 T cell
populations, they decay thereafter. Thus, after transfer the
V2-T3.70+ population
becomes the less represented T cell subset (Fig. 3C). These
single V2-T3.70+ TCR
cells, recovered late after transfer, become refractory and proliferate
poorly upon in vitro stimulation with the HY-specific peptide or Con A
(Fig. 3D) (26). The fraction of dual
V2+T3.70+ cells
increased at a similar rate and continued to expand up to day 14 after
transfer, but once they reached their peak of growth, their numbers did
not decline and remain constant. The dual-receptor cells that persisted
after expansion proliferated better than the single
V2-T3.70+ cells to the
in vitro stimulation by the HY peptide (Fig. 3, B and
D). However, this response was 10-fold lower than that of
control naive CD8 cells from MoaHY female mice (data not shown).
Finally, the fraction of
V2+T3.70- cells
augmented 10-fold less at a much slower rate (Fig. 3C);
i.e., they mimic the growth of MoP14 cells transferred into
CD3-/- female hosts (Fig. 3A). We conclude that mature dual-receptor cells show efficient in vivo responses but are less susceptible to the induction of peripheral tolerance than the single TCR-expressing cells. Indeed, after in vivo stimulation with an excess of Ag, they are not replaced by other cell populations and retain a partial responsiveness when stimulated in vitro with the specific peptide.
Competitive ability and immune responses of DTg CD8 cells from male mice
We have investigated whether the presence of two TCR transgenes
could rescue cells from deletion in the presence of male HY self-Ag.
Comparing T cell development in the thymus of MoaHY and DTg male mice,
we found that the presence of the second V2 TCR transgene rescues a
significant fraction of cells into the double positive (DP) compartment
(35). This allows the selection of cells co-expressing
both V2 and low levels of HY-specific VT3.70 into the SP CD8 T
cell compartment (35). At the periphery of the DTg males, we recovered
significant numbers of CD8+ T cells (12 x
106), of which the majority (80%) express two
TCR chains (Fig. 4A).
In contrast to DTg females (Fig. 1A), single
V2+T3.70- cells are
more abundant (15–20%) and
V2-T3.70+ cells are
rare (
2%). A significant fraction of the
CD8+T3.70+ cells are
activated, i.e., they express intermediate or high levels of CD44 (Fig. 4B).
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90% of the cells were from DTg
origin (Fig. 5A). The fraction
of MoaHY and single
V2-T3.70+ cells is
strongly reduced, whereas the
V2+T3.70- cells become
more abundant (Fig. 5A). These findings show a preferential
selection of the cells that lose expression of the HY-specific
VT3.70, suggesting that, when in the presence of self-Ag, dual
TCR CD8 T cells expressing the VT3.70 aHY chain are counter
selected and less fit to integrate the peripheral T cell pool.
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B) than CD8 cells from DTg
female donors (see Fig. 3B). After transfer, the fraction of
the single V2+T3.70-
expressing donor cells increased both in male and female adoptive hosts
(Fig. 5C). In vitro, upon stimulation with the
Scmy-3 HY-specific peptide, the response of the T cells from
DTg males was of lower intensity and delayed compared with the T cells
from female DTg mice, but it was significantly detectable in the
presence of high concentrations of the stimulating ligands (Fig. 6A). The T cells from male DTg
mice up-regulated CD69 expression after stimulation with the HY peptide
(Fig. 6B). In contrast, the CD8 T cells from DTg males did
not proliferate upon stimulation with the gp33-41 peptide (Fig. 6C). The fraction of T cells that up-regulate CD69 after
gp33-41 stimulation was reduced (Fig. 6D) compared with T
cells from DTg females (data not shown). Overall, these results show
that CD8 T cells from DTg male mice, though functionally impaired,
retain some functional capabilities in that they can expand in vivo and
proliferate in vitro when stimulated with high concentrations of the
specific peptide.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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- and the -chains of the anti-LCMV P14 TCR
and of the anti-male Ag aHY TCR (15, 20). We have
reported that, in these DTg mice, most CD8 T cells express only the
TCR chain from the aHY transgene. By comparing the mRNA
species for both TCR chains, we previously have shown that, in DTg T
cells, the anti-LCMV TCR chain transcripts were
less abundant (35), suggesting that the earlier and higher expression
of the aHY TCR chain inhibits the late transcription of the
anti-LCMV TCR chain. As a result of this process, 80% of the
peripheral CD8 T cells from the DTg mice express one TCR associated
with two TCR chains. Therefore, these DTg mice provide a unique
model for studying the functional behavior of the dual-TCR CD8 T
cells. Here, we investigated the peripheral selection and competitive
survival fitness of these dual-receptor CD8 T cells.
Exposure of mature naive DTg cells from female mice to the male HY Ag
in vivo, i.e., after transfer into male hosts, resulted in the
selective expansion of both HY-specific single
V2-T3.70+ and dual
V2+T3.70+ cells. The
immune response of single
V2-T3.70+, however, was
more efficient, as indicated by their faster rate of expansion. Thus,
the lower surface expression of the aHY-specific TCR may decrease the
overall T cell avidity to the HY Ag and render the dual
V2+T3.70+ cells less
efficient responders (27). A similar expansion of single
LCMV-specific V2+T3.70-
cells was observed upon immunization of the DTgmice with the
virus (N.L., unpublished observations). In the DTg mice, the single
V2-T3.70+ aHY-specific
cells were susceptible to the tolerogenic effects of excess Ag, because
7 days after transfer into male hosts, they became refractory and
unable to proliferate upon in vitro stimulation (26).
Later, in vivo, both dual
V2+T3.70+ cells and
V2+T3.70-
non-HY-specific cells replaced the "anergic"
V2-T3.70+ cells (Fig. 3). Indeed, tolerant MoaHY CD8 T cells have been shown to persist when
alone (28) (Fig. 3) but are rapidly substituted when in
the presence of other competing populations (26, 29). In
contrast, the dual-receptor cells exposed in vivo to an excess of male
Ag, though still susceptible to the induction of tolerance, were not
substituted and did not disappear later after transfer. The fact that
these tolerant dual-TCR cells persist and are not replaced may allow
them to exert important regulatory functions in vivo
(30).
We have shown that the presence of a second TCR transgene reduces the
level of surface expression of the aHY-specific TCR, allowing the
appearance of significant numbers of DP thymocytes and SP
TCRhighCD8+ T cells in male
DTg mice (35). In DTg males, peripheral CD8+
cells express two V chains, but in contrast to female DTg mice, the
single T3.70+ cells are rare and the single
V2+ cells are more abundant. Overall, the
presence of the HY Ag leads to the counterselection of cells bearing
high levels of the aHY-specific receptors in DTg mice. What functional
roles do the dual-receptor-expressing T cells, which develop in the
presence of self-Ag, play? We show that, although the presence of a
second TCR permits the development and emigration of mature CD8 T cells
expressing a self-reactive TCR, these peripheral dual-receptor T cells
are functionally tolerant. They express low levels of CD8 and of the
aHY-specific TCR, and like CD8 T cells from Rag+
aHY Tg and MoaHY males, proliferate poorly to high doses of ligand
(15, 26, 28) and up-regulate CD69 expression, mimicking
partial agonistic responses (31). In vivo exposure of DTg
cells from male mice to the HY Ag, i.e., after transfer into male
hosts, results in a limited increase in the number of DTg cells.
Despite the increased expression of the P14 TCR chain, the
dual-receptor CD8 cells from male mice are unable to proliferate to the
LCMV gp33-41 peptide. A significant fraction of the dual-receptor cells
from male mice, however, express the activation/memory CD44 marker and
produce 
-IFN (data not shown) and IL-10 mRNAs (30),
suggesting that these tolerant cells are not fully anergic and may have
important regulatory functions. These findings support the notion that
tolerance induction, rather than a state of complete functional
"anergy" (20), represents a change in the functional
behavior of the cell (30), which may be due to changes in
the thresholds of cell activation.
Using a competitive repopulation strategy, we directly accessed the
accumulation of dual- and single-receptor CD8 T cells in the peripheral
pools of different BM chimeras. When alone, T cells from DTg and single
transgenic donors show similar behavior and generate peripheral pools
of similar size. When mixed in the same host, CD8 T cells colonized the
peripheral pools, following a hierarchy in which MoP14 >
MoaHY = DTg cells. In these experiments, the advantage of the P14
cells may be due to their ability to recognize cross-reactive Ags
present at the periphery but absent in the thymus. Indeed, after
transfer into syngeneic T cell-deficient hosts, the P14 CD8 T cells
express CD44+ and expand moderately
(32). In agreement with these observations, we found that,
in mixed DTg vs MoaHY chimeras, the fraction of single
V2+T3.70- cells
increases in the peripheral pool, again suggesting a broader reactivity
of the cells expressing the V2 TCR. We must mention that, in
the mixed DTg vs P14 chimeras, the fraction of the same
V2+T3.70- of DTg origin
decreases. In these chimeras, it is possible that the
V2+T3.70- cells of DTg
origin are out-competed by the V2+ cells of
P14 origin. Thus, CD8 T cells expressing the P14
V8.1+V2+ TCR are more
fit than
V8.2+V2+-expressing
cells from the DTg donors, and they both out-compete the
aHY-specific
V8.2+VT3.70+ cells.
These results suggest that fine TCR specificity and/or promiscuity may
be determinant for the peripheral survival and accumulation of CD8 T
cells. They also indicate that dilution of each specific TCR may reduce
the survival fitness of the dual-TCR CD8 T cells, favoring the
occupation of peripheral pools by single-receptor T cells. Lymphocyte
competition for survival signals is likely part of the homeostatic
processes that regulate the peripheral T cell pool size (33, 34). Comparing peripheral CD8 T cells in male MoaHY and DTg
mice, we found that, in contrast to MoaHY males where
TCR+CD8- (DN) cells
represent 60% of the peripheral TCR+ cell pool
(15), in DTg male mice most peripheral
TCR+ cells are CD8+. These
results suggest that an optimal level of signal is required to ensure
peripheral T cell survival. Successful survival may reflect a process
of "adaptation" of lymphocyte populations to the host environment.
Thus, according to the antigenic environment, surviving T cell
populations express the correct levels of TCR and coreceptors; i.e.,
low TCR and CD8 levels compensate for an excess of ligand, high TCR
expression for the lack of CD8 coreceptors, etc.
In normal mice, TCR inclusion occurs in 30% of T cells, which may
represent an autoimmune hazard. Using double-TCR Tg mice, we
characterized the functional behavior of dual-receptor CD8 T cells.
Naive dual-receptor cells, which develop in absence of self-Ag, respond
to Ag immunization, though less efficiently than single-receptor T
cells. The naive dual-receptor cells remain sensitive to induction of
peripheral tolerance after exposure to high levels of self-Ag. However,
the tolerant dual-receptor cells are more resistant to in vivo
replacement by nonspecific T cell populations than single-receptor
cells. They persist and, therefore, may exert important regulatory
functions in vivo. We found that the presence of a second TCR allows a
significant number of dual-receptor CD8 T cells expressing a
self-reactive receptor to escape central deletion by self-Ag. These
nondeleted cells migrate to the peripheral pools but are not fully
competent to respond to cognate stimuli. The ensemble of these
characteristics may contribute to a decrease in the autoimmune hazard
that dual-receptor cells could represent in normal physiological
conditions.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Antonio A. Freitas, Lymphocyte Population Biology Unit, Unité de Recherche Associée, Centre National de la Recherche Scientifique, 1961 Institut Pasteur, 25 Rue du Dr. Roux, 75015 Paris, France. E-mail address: afreitas{at}pasteur.fr
3 Abbreviations used in this paper: Tg, transgenic; LCMV, lymphocytic choriomeningitis virus; DTg, double transgenic; BM, bone marrow; LN, lymph node; DN, double negative; SP, single positive; DP, double positive.
Received for publication July 13, 2001. Accepted for publication September 21, 2001.
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  M.-E. Marquez, W. Ellmeier, V. Sanchez-Guajardo, A. A. Freitas, O. Acuto, and V. Di Bartolo CD8 T Cell Sensory Adaptation Dependent on TCR Avidity for Self-Antigens J. Immunol., December 1, 2005; 175(11): 7388 - 7397. [Abstract] [Full Text] [PDF]
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 A. G. Schrum and L. A. Turka The Proliferative Capacity of Individual Naive CD4+T Cells Is Amplified by Prolonged T Cell Antigen Receptor Triggering J. Exp. Med., September 16, 2002; 196(6): 793 - 803. [Abstract] [Full Text] [PDF]
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), MoaHY (
), and DTg (
)
female mice were transferred into B6.CD3
) or female (