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Unite du Développement des Lymphocytes, Centre National de la Recherche Scientifique, Unité de Recherche Associée 1961, Institut Pasteur, Paris, France
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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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The peripheral T cell repertoire is maintained by thymic output of
naive T cells and by self-renewal of part of the peripheral T cell pool
(4). In the mouse, export of 
106
T cells/day from the thymus to the periphery (5) requires
the loss of similar numbers of peripheral resident T cells. Recent
observations suggest that this peripheral T cell loss is mostly due to
the replacement of naive resident T cells by recent thymic emigrants
(6, 7). Furthermore, studies using TCR-transgenic animal
models conclude that the naive and the activated/memory CD8 T cell
pools are independently regulated (8, 9).
To date, it is neither known how the naive and the naturally activated/memory CD4 T cell pools are regulated nor what the relative contribution of exogenous and endogenous Ags in promoting peripheral CD4 T cell self-renewability is.
Peripheral naive CD4 T cells can be identified by high surface density of the CD45RB molecule, and the transition from a naive to an Ag-experienced state is accompanied by down-regulation of CD45RB (10).
Based on this marker, several groups reported that transfers of naive
CD4 T cells into T and B cell-deficient, syngeneic recipients leads to
the development of a lethal form of inflammatory bowel disease
(IBD)5 (11, 12). This
disease is caused by massive Th1-mediated immune responses in the gut
developed against (or promoted by) local Ags which result in high
levels of IFN-
and TNF-
in the sick animals
(12, 13, 14, 15). Moreover, naive CD4 T cells were unable to
induce IBD in the absence of IFN- (14, 16).
In this experimental system, naturally activated/memory CD4 T cells did not trigger disease, and cotransfer of both naive and activated cells revealed the ability of the latter to prevent the onset of IBD (11, 12, 13, 14). Further studies showed that the protective effect was dependent on TGF-ß and/or IL-10 (14, 17, 18, 19, 20), but not on IL-4 (18).
These experiments demonstrated the importance of T cell-dependent regulatory mechanisms in the control of the magnitude of mucosal immune responses, but to date it is unknown at which level regulation occurs: differentiation of Th1 precursors, migration of aggressive T cells, or expansion of cells capable of inducing IBD.
In this study, we investigated the possibility that the regulatory events implicated in mucosal immune responses illustrate a general mechanism responsible for maintaining the systemic equilibrium between functional subsets of peripheral T cells.
To evaluate the potential for expansion of naive and activated/memory CD4 T cell subsets and their respective ability to reconstitute Rag-20/0 recipients, we used T cells from donor strains congenic for the CD45 (Ly5) marker to follow both populations in cotransfer experiments.
We show that the expansion potential of naive cells, once activated, is not limited by natural resources and that naturally activated/memory T cells regulate the size of the activated CD4 T cell pool. The results support the notion that CD4 T cell expansion in Rag-20/0 recipients is largely dependent on exogenous Ags.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 mice were obtained from Janvier (Le Genest-St-Isle, France). C57BL/6 Ly5.1 and C57BL/6 Rag2-deficient (Rag20/0) mice were purchased from CDTA (Orleans, France) and were bred either under specific pathogen-free (SPF) or conventional conditions in our animal facilities.
BALB scid mice were purchased from Charles River Breeding Laboratories (Saint Aubin les Elbeuf, France) and maintained under SPF conditions. BALB/c germfree (GF) mice were purchased from Centre de Développement des Technique Avancées pour L’Expérimentation Animale and used immediately upon arrival.
Antibodies
The following mAbs were used: anti-Ly5.1-FITC (clone A.20); anti-CD4-FITC, -PE, or -APC (L3T4); anti-CD8-PE (53-6.7); and anti-CD45RB-PE (23G2). All Abs were purchased from PharMingen (San Diego, CA).
T cell preparations
Splenic single-cell suspensions were first enriched for CD4+ cells either by depletion of B cells and macrophages using Dynabeads (Dynal, Oslo, Norway) or by positive selection on miniMacs columns (Miltenyi Biotec, Bergisch-Gladbach, Germany) according to the manufacturers’ instructions. In brief, for cell depletion, suspensions were incubated with anti-CD8 and anti-B220 rat IgG Ab for 20 min at 4°C followed by sheep-anti-rat-Ig-Dynabeads (M450) for 20 min at 4°C before separation in a magnetic field. For positive enrichment of CD4+ cells before sorting, cells were first incubated with biotinylated anti-CD4 Abs for 20 min on ice in PBS supplemented with 0.5% FCS and then incubated in the same buffer with streptavidin-microbeads for 15 min. The magnetically labeled positive fraction was retained on a miniMacs column. After enrichment, the cells were labeled with FITC-labeled anti-CD4 (or streptavidin-FITC) and anti-CD45RB-PE Ab for 20 min on ice and then sorted on a FACStarPlus (Becton Dickinson, Mountain View, CA). The 40–50% of CD4+ cells which stained brightest and the 15–30% of CD4+ cells staining the lowest for CD45RB were sorted as CD4+CD45RBhigh and CD4+CD45RBlow populations, respectively. The purity of the sorted populations was routinely >97%.
For the preparation of intestinal cell suspensions, large and small intestines were first flushed extensively to eliminate the lumen content and then longitudinally opened and cut into 1–2-cm pieces. These were incubated twice in prewarmed Optimem medium (Life Technologies, Rockville, MD) containing 5% FCS and 450 U of collagenase (Sigma, St. Louis, MO) for 20 min at 37°C. After filtering through gauze, lymphoid cells were isolated on a 40% Percoll gradient. The cells were then washed and stained for fluorocytometric analysis.
Cell transfers
C57BL/6 Rag-20/0 mice were injected i.v. with 3–6 x 105 CD4 T cells from either CD45RBhigh or CD45RBlow subpopulations. When both populations were cotransferred, Ly5.1+ and Ly5.2+ donor cells were used (at a ratio of 1:1). When C.B.-17-scid recipients were used, the two CD4 T cell subsets were prepared from the spleens of BALB/c GF animals.
Flow cytometric analysis
Cells from spleen, lymph nodes, or intestine were incubated for 20 min at 4°C in microtiter plates with 50 µl of the appropriate Ab preparations in PBS supplemented with 3% FCS and 0.001% azide. Where possible, one million cells were stained. Alternatively, the whole organ cell suspension was used. The Ab concentrations used were tested for optimal stainings of splenic control samples before use in experiments. Dead cells were excluded from the analysis by propidium iodide. Blood samples were first stained with appropriate Abs before lysing erythrocytes with FACS lysing solution (Becton Dickinson). Flow cytometric analysis was performed on a FACScan (Becton Dickinson) and analyzed using CellQuest software (Becton Dickinson).
Statistical analysis
Analysis was performed using the unpaired t test. The data were considered significantly different when p values were <0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Splenic CD4 T cells of donor C57BL/6-Ly5.2 and C57BL/6-Ly5.1 mice were separated into CD45RBlow and CD45RBhigh subsets (hereafter referred to as RBlow and RBhigh, respectively). Adult Rag-20/0 mice were i.v. injected with 3 x 105 cells of either cell population alone or with both populations, distinguishable by the Ly5 allotype marker, at a ratio of 1:1. Weight was recorded during the following weeks and mice were regularly bled.
In agreement with previous studies (11, 12, 14), most mice
injected with RBhigh CD4 T cell populations
started losing weight by the end of the second week after transfer, and
signs of diarrhea were apparent by the third week. Rectal prolapse
occurred later and was observed in most animals. In contrast, animals
injected with RBlow CD4 T cells gained weight and
with one exception, no signs of wasting disease were observed. The
protective role of RBlow CD4 T cells was
efficient since only 3 of 17 mice that received this population, either
alone or along with RBhigh, became sick (Fig. 1
A).
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Fig. 1
C shows the absolute number of T cells in the
indicated organs for each individual recipient. In mice injected with
RBlow CD4 T cells, analyzed mostly 6 mo after the
transfers, the majority of the T cells (range, 0.5–2.5 x
106) was found in the spleen (Fig. 1C). A small fraction (<0.5 x
106) was present in mesenteric lymph nodes,
whereas essentially no cells were recovered from the wall of both the
small and large intestine which were normal in appearance. T cells were
recirculating in the blood at low numbers (range, 2–10 x
104/ml), and these values were similar to those
recorded as early as 10 days posttransfer (data not shown).
In contrast, a typical IBD colon with a thickened wall was observed in
every recipient of RBhigh CD4 T cells, which were
mostly analyzed after 2 mo. Correspondingly, high (although variable)
numbers of T cells were recovered from the gut (range, 0.2–5 x
106 T cells). This was associated with a very
high frequency (15–40%) of TNF-- and IFN--producing CD4 T cells
(data not shown). Although splenic T cell numbers were not
significantly different from those in the group of
RBlow recipients, 3.5 times more CD4 T cells on
average were found in the blood. This significant difference
(p = 0.0007) in the numbers of PBLs correlated
with the onset of weight loss (data not shown). As seen in Fig. 1B, the total numbers of CD4 T cells (representing the sum
from all analyzed organs) were on average only 2–3-fold higher than
those recorded for recipients of RBlow CD4 T
cells. This difference is significant (p =
0.0006) and is mostly accounted for by the number of cells recovered
from the intestinal wall.
Finally, in the group cotransferred with both CD4 subsets, the originally naive RBhigh CD4 T cell population expanded merely to a similar extent as the RBlow T cells, and with a similar pattern of localization, with low or no T cell recovery from the intestinal wall. In the blood, the RBlow:RBhigh ratio of the injected cohort was maintained and both populations were recirculating in low numbers.
Clearly, the presence of RBlow CD4 T lymphocytes limited the degree of expansion of the naive T cell pool (p = 0.0042, comparing total cell numbers for RBhigh injected either alone or along with RBlow), and very markedly inhibited their migration and/or expansion at the level of the gut. These differences do not appear to reflect distinct kinetics since the same results were observed when mice were analyzed at comparable time points (data not shown4). As pointed out by others (11), in the two groups of mice that received RBhigh CD4 T cells, >90% of these T cells acquired an activated/memory phenotype in all organs analyzed (data not shown), indicating that most of the cells that survived in the recipient encountered Ag.
In summary, the results show that 1) RBlow CD4 T cells seem to have a relatively limited potential for expansion (on average 6-fold the number of injected cells) with autonomic dynamics, i.e., independent of the presence of naive cells; 2) naive CD4 T cells, once activated, have a higher potential for expansion and the difference in the level of peripheral replenishment of the hosts is due to immune responses at the level of the gut, which are also reflected in the number of blood circulating T cells; and 3) naturally activated/memory CD4 T cells regulate the size of the peripheral pool of activated CD4 T cells in the reconstitution of Rag-20/0 mice.
Peripheral expansion of CD45RBhigh CD4 T cells depends on the age of the recipient
In the next set of experiments, we studied the survival and/or expansion of naive CD4 T cells in an environment where stimulation by exogenous Ags, in particular those related to bacterial colonization of the gut, was reduced.
RBhigh CD4 T cells were injected into
Rag-20/0 newborns within 24 h after birth.
As shown in Fig. 2A, during
the first 3 wk of age, injected animals developed in a similar manner
as uninjected controls. From then on, all injected mice grew slower and
barely gained weight. Signs of diarrhea and bleeding became apparent,
although no death occurred during a period of 2.5 mo.
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C
compares the numbers of T cells recovered from the indicated organs of
newborn recipients with those plotted in Fig. 1 which correspond to
adult Rag-20/0 recipients injected with the same
number of RBhigh CD4 T cells. As shown,
significantly higher T cell numbers were obtained in recipients that
received the T cell cohort as newborns (p =
0.0074), particularly from the intestines (6-fold on average;
p = 0.0088). CD4 T cell numbers were also increased in
the mesenteric lymph nodes (p = 0.0165) and,
although not significantly, in the blood. It is noteworthy that in 5 of
10 mice injected as newborns, the total number of CD4 T cells varied
between 26 and 57 million cells, representing roughly 100–200 times
the number of injected cells. Given the important contribution of intestinal T cells to the level of peripheral T cell reconstitution and the absence of clinical signs of IBD in newborn recipients before the fourth week after transfer, we addressed the possibility that the bulk of what is called peripheral T cell expansion is the result of immune responses, particularly at the level of the gut. If so, T cell expansion should be limited and the majority of the injected RBhigh CD4 T cells should remain in a resting phenotype when transferred into very young recipients and analyzed before the period of weaning.
Fig. 3A shows the total number
of T cells recovered 2 and 3 wk after the transfer of
RBhigh CD4 T cells into recipients of 4, 7, or 10
days of age. Very few cells were detected 2 wk after transfer (when the
mice were 17, 20, or 23 days old) in the peripheral lymphoid organs in
all groups of mice, and no cells were recovered from the gut (data not
shown). In contrast, massive expansion had occurred after 3 wk in the
10-day-old recipients, which at the time of sacrifice were 1-mo old. As
predicted, no increase in T cell numbers was yet observed in the
4-day-old recipients whereas in the intermediate group 1.5 million
cells were scored. Most T cells in the spleen of the youngest
recipients still expressed high levels of the CD45RB molecule,
compatible with a resting phenotype (Fig. 3B).
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The naturally activated splenic CD45RBlow CD4 T cell pool contains T cells that are capable of inducing IBD
As described, RBlow CD4 T cells contain
regulatory T cells, which protect lymphocyte-deficient recipients from
RBhigh-induced IBD. Nevertheless, one of nine
RBlow recipients in our experiments showed signs
of disease (Fig. 1A), suggesting the presence of primed,
aggressive T cells.
When the same transfer experiments done under SPF-conditions were
performed in Rag-20/0 recipients kept continually
under conventional animal housing conditions, all mice injected showed
weight loss and diarrhea shortly after transfer, including those of the
group that received RBlow CD4 T cells only (Fig. 4A), whereas noninjected
control Rag-20/0 mice did not show signs of
disease (data not shown). The severity of the disease was much more
pronounced and animals had to be sacrificed within a period of 7
wk.
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C), with comparable T cell numbers between the three
groups of recipients. In some cases, >107 T
cells were recovered from the spleen (Fig. 4C). The present results show that the pool of naturally activated splenic CD4 T cells contains not only regulatory cells, but also primed, potentially aggressive cells.
CD45RBlow CD4 T cells of GF mice control naive CD4 T cell-induced IBD
The origin and Ag recognition of natural regulatory T cells is to date unknown. Mice kept under GF and Ag-free conditions contain almost normal numbers of naturally activated T and B cells in the spleen, including functionally differentiated effector cells (22).
Here, we studied the ability of naturally activated
RBlow CD4 T cells from GF mice to suppress the
development of IBD if cotransferred with naive CD4 T cells. GF donor
BALB/c mice were sacrificed immediately upon arrival and several
lymphoid organs were analyzed to ascertain that the animals were in a
GF state. Numbers of splenic CD4 T cells were similar to those in SPF
mice, and 5.5 and 14.4% of these were, respectively, low and
intermediate for expression of the CD45RB molecule (Fig. 5A).
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Finally, serum levels of total IgG were on average 56-fold reduced, whereas three times more IgM was detected in GF mice, as compared with normal SPF animals. We conclude that the characteristics of the donor GF mice used in our studies were in agreement with previous descriptions.
Sorted RBlow CD4 T cells obtained from the spleens of BALB/c GF mice were coinjected with RBhigh CD4 T cells from the same GF mice into C.B.-17-scid recipients. As controls, each population was transferred alone.
GF naive CD4 T cells were particularly aggressive to the recipients
since most animals started losing weight 10–12 days after transfer,
and all mice had to be sacrificed within the next few days. As shown in
Fig. 5B, recipients of RBlow CD4 T
cells remained at normal weight until sacrifice. In the group
cotransferred with both CD4 T cell subsets, although fluctuation of
weight was observed in some mice, all animals were otherwise healthy,
without signs of diarrhea or bleeding. Two months after transfer at the
time of sacrifice, the large intestine was, in all recipients,
macroscopically indistinguishable from that of normal uninjected hosts
or from recipients of RBlow CD4 T cells. As
expected, essentially no T cells were recovered from the small and
large intestines (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Total T cell recoveries in SPF recipients of RBhigh CD4 T cells were variable and in the range of 8–200 times the number of injected lymphocytes. Since no more than 2–10% of the injected cells survived in the host 24 h after transfer, we estimate that the population underwent 6–11 rounds of division (generating up to 10,000 times the number of surviving cells). The magnitude of expansion was dependent on the capacity of the hosts to survive IBD. Regardless of the degree of expansion, most of the recovered T cells were CD45RBlow, indicating that they were activated in the recipients. Our data thus present the possibility that these expansions, which have sometimes been interpreted as the result of nonspecific homeostatic mechanisms, are actually Ag driven and result from classical immune responses to environmental Ags. This is supported by the observation that activation and expansion of the RBhigh CD4 T cells was negligible during the first 3 wk after transfer into newborn recipients. The correlation found between the age of the recipient and significant expansion of activated cells suggests that this response is largely dependent on colonization of the intestine by diversified bacterial flora, which is known to occur after weaning (21).
In this context, it should be noted that transfer of GF-derived T cells into GF nude mice resulted in limited peripheral replenishment of the hosts, with low T cell numbers in the spleen and no T cell colonization of the gut (A. Bandeira, C. Heusser, and A. Coutinho, unpublished observations). Other explanations for the lack of T cell expansion in newborn recipients, such as the lack of differentiated or functional antigenic niches, or limited nonspecific resources during early development, cannot be excluded at this point. However, they seem unlikely to account for the present results since a number of immune responses, including antiviral responses, can be induced after natural or experimental immunization of euthymic newborn individuals (23).
Despite the relatively limited expansion (four to seven rounds of division) under SPF conditions, the naturally activated splenic CD4 T cell pool also contains cells capable of extensive proliferation in vivo. This capacity was revealed when RBlow CD4 T cells were transferred into non-SPF recipients. Cells with regulatory activity thus represent a fraction of the heterogeneous RBlow CD4 T cell population which also contains aggressive cells. It is likely that these cells are reactive (or cross-reactive) to environmental, presumably intestinal, Ags. The reasons for the inefficiency of regulatory T cells to prevent disease in this case were not investigated. They could be the result of exogenous antigenic load in the recipients favoring reactivation of primed aggressive cells or be related to the repertoire of regulatory T cells, since they were originally selected in a different antigenic environment.
The persistency of low numbers of peripheral T cells in SPF-mice
injected with naturally activated/memory CD4 T cells, or coinjected
with naive cells, is remarkable. This demonstrates that the size of the
activated peripheral CD4 compartment is regulated, at least partially,
at the level of growth control of activated CD4 T cells. This in turn
may result in regulation of the state of differentiation of aggressive
cells. Examples where helper T cell differentiation is controlled by
the cell cycle include the finding that the frequency of
IFN--expressing cells increases with successive cell divisions
(24).
Despite a chronic state of lymphopenia, in an otherwise nonlimiting environment for Ag and natural resources (activated T cells may divide up to 11 times), compensatory mechanisms that try to re-establish total lymphocyte numbers do not seem to operate, at least in Rag-20/0 hosts. Peripheral T cell expansions in alymphoid animals or in situations of lymphopenia (following thymectomy or consequent to certain viral infections, e.g., HIV), rather than reflecting ("reconstitution") or ("regeneration") of the peripheral immune system, may simply represent unbalanced immune responses of activated T cells against exogenous Ags, thus revealing a certain level of deficiency of the peripheral regulatory T cell pool.
The survival of peripheral naive T cells requires continuous signals through the TCR which are MHC restricted (25). The nature of the MHC-bound peptides in this phenomenon of peripheral positive selection was recently addressed by several groups. Since in all cases, the studies were based on T cell transfers into lymphopenic or alymphoid recipients, these studies addressed expansion rather than survival of transferred T cells.
For CD4 T lymphocytes, Bender et al. (26) concluded that the set of peptides promoting peripheral T cell expansion is distinct from that responsible for thymic selection. Our present results are in agreement with these observations and suggest that the bulk of T cell expansion is driven by exogenous ligands.
Using a similar experimental strategy, a second group reached the opposite conclusion that peripheral expansion and thymic selection involve similar peptides. Their major argument is based on the observation that H-2 M- CD4 T cells proliferate more than wild-type B6 T cells when transferred into H-2 M- recipients (27). The same authors had previously published, however, that H-2 M- CD4 T cells proliferate strongly in vitro against wild-type B6 but not H-2 M- stimulators (28). It is therefore to be expected that H-2 M- CD4 T cells, if transferred into irradiated B6 mice, will proliferate more extensively than in H-2 M- hosts, and thus rather support the opposite conclusion. It is therefore difficult to conclude that the in vivo proliferation of H-2 M- CD4 T cells in H-2 M- hosts is driven by self-ligands.
For CD8 T cells, Goldrath and Bevan (29) suggested that peripheral T cell expansion requires specific recognition of self-peptide/MHC complexes similar to those involved in thymic maturation. Thus, an antagonist peptide, capable of promoting thymic-positive selection, induced significant T cell expansion (though poor functional differentiation) when expressed in the periphery of alymphoid recipients. A marked difference was nevertheless apparent when this peptide was compared with the high avidity one. In addition, several surface markers remained unchanged upon recognition of the antagonist peptide as compared with resting T cells. It is therefore possible that the effect now observed in vivo is equivalent to the one observed in fetal thymic organ cultures that led to the designation of antagonist peptide. We think that it is a matter of speculation whether this particular peptide is representative of the selecting ligands in the thymus of normal mice. In addition, Kieper and Jameson (30), using the same TCR-transgenic mice, report that other peptides capable of promoting positive selection seem unable to induce peripheral expansion of these transgenic T cells. Similarly, anti-H-Y TCR transgenic CD8 T cells fail to expand when transferred into female Rag-2% recipients (9).
The variability in the behavior of different TCR-transgenic mice is to be expected given the possible differences in TCR avidity and the lack of quantitative information on the density of their respective ligands in vivo. Analysis of the behavior of normal polyclonal T cell populations should provide a global and more physiological picture of the role of endogenous vs exogenous Ags in promoting peripheral T cell survival and expansion.
Our experiments did not address possible effects of natural regulatory T cells on the size of the naive CD4 T cell pool which is obviously dependent on thymic output (7, 31). For CD8 T cells, it was suggested that the pools of naive and activated/memory cells are independently regulated (8). It remains unknown whether T cell-dependent regulatory mechanisms, similar to those here described for CD4 T cells, also operate in the homeostasis of the activated/memory CD8 T cell compartment.
Regulatory CD4 T cells have also been described in experimental systems of tolerance and autoimmune disease (for review, see Ref. 32). It is not yet known whether these various populations have a common origin, development, or function. Several studies using different experimental systems have shown that CD4+CD8- thymocytes can also exert regulatory function (33, 34, 35, 36, 37). The intrathymic generation of regulatory T cells (37) supports the idea that these cells are self-reactive (38).
The self-reactive nature of at least part of the peripheral regulatory T cells is supported by our present results showing that GF mice contain effector CD4 T cells capable of preventing IBD. A formal demonstration of the absence of exogenous Ag stimulation in GF mice is difficult to provide. One should note, however, that GF mice have similar numbers of activated splenic T cells as compared with SPF animals (22), whereas a 100–200-fold reduction in the number of T cells in the gut-associated lymphoid tissue is observed. If exogenous Ags were responsible for such natural activation, a similar reduction in the number of activated splenic T cells would be expected. It is nevertheless striking that GF-derived activated T cells prevent IBD when cotransferred with naive T cells into C.B.-17-scid recipients, which harbor a bacterial flora different from the one responsible for the selection of the regulatory T cells in GF mice.
It is possible that the same pool of regulatory cells controls not only the magnitude of immune responses to exogenous Ags, but maintains natural tolerance to tissue-specific Ags as well. Situations of lymphopenia may thus lead to the disruption of these regulatory circuits and allow the differentiation and/or abnormal expansions of aggressive T and B cells and the onset of autoimmune disease.
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Acknowledgments |
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Footnotes |
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2 O.A. and O.B.-D. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Antonio Bandeira, Unité du Développement des Lymphocytes, Institut Pasteur, 28, rue du Docteur Roux, 75724 Paris Cedex 15, France. E-mail address:
4 The data were made available to the reviewers.
5 Abbreviations used in this paper: IBD, inflammatory bowel disease; SPF, specific pathogen free; GF, germfree.
Received for publication October 1, 1999. Accepted for publication January 27, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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knockout mice do not induce wasting disease. J. Autoimmun. 10:455.[Medline]
ß+CD4+ thymocytes expressing L-selectin mediate "active tolerance" in the nonobese diabetic mouse. J. Immunol. 161:2620.This article has been cited by other articles:
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 M. Miyara, Z. Amoura, C. Parizot, C. Badoual, K. Dorgham, S. Trad, M. Kambouchner, D. Valeyre, C. Chapelon-Abric, P. Debre, et al. The immune paradox of sarcoidosis and regulatory T cells J. Exp. Med., February 21, 2006; 203(2): 359 - 370. [Abstract] [Full Text] [PDF]
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M. Mesel-Lemoine, M. Cherai, S. Le Gouvello, M. Guillot, V. Leclercq, D. Klatzmann, V. Thomas-Vaslin, and F. M. Lemoine Initial depletion of regulatory T cells: the missing solution to preserve the immune functions of T lymphocytes designed for cell therapy Blood, January 1, 2006; 107(1): 381 - 388. [Abstract] [Full Text] [PDF]
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O. Annacker, J. L. Coombes, V. Malmstrom, H. H. Uhlig, T. Bourne, B. Johansson-Lindbom, W. W. Agace, C. M. Parker, and F. Powrie Essential role for CD103 in the T cell-mediated regulation of experimental colitis J. Exp. Med., October 17, 2005; 202(8): 1051 - 1061. [Abstract] [Full Text] [PDF]
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J. D. Fontenot, J. L. Dooley, A. G. Farr, and A. Y. Rudensky Developmental regulation of Foxp3 expression during ontogeny J. Exp. Med., October 3, 2005; 202(7): 901 - 906. [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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L. Pace, C. Pioli, and G. Doria IL-4 Modulation of CD4+CD25+ T Regulatory Cell-Mediated Suppression J. Immunol., June 15, 2005; 174(12): 7645 - 7653. [Abstract] [Full Text] [PDF]
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 S. Zelenay, T. Lopes-Carvalho, I. Caramalho, M. F. Moraes-Fontes, M. Rebelo, and J. Demengeot Foxp3+ CD25- CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon homeostatic expansion PNAS, March 15, 2005; 102(11): 4091 - 4096. [Abstract] [Full Text] [PDF]
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T. Barthlott, H. Moncrieffe, M. Veldhoen, C. J. Atkins, J. Christensen, A. O'Garra, and B. Stockinger CD25+CD4+ T cells compete with naive CD4+ T cells for IL-2 and exploit it for the induction of IL-10 production Int. Immunol., March 1, 2005; 17(3): 279 - 288. [Abstract] [Full Text] [PDF]
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C. J. Workman and D. A. A. Vignali Negative Regulation of T Cell Homeostasis by Lymphocyte Activation Gene-3 (CD223) J. Immunol., January 15, 2005; 174(2): 688 - 695. [Abstract] [Full Text] [PDF]
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H. C. Dujardin, O. Burlen-Defranoux, L. Boucontet, P. Vieira, A. Cumano, and A. Bandeira Regulatory potential and control of Foxp3 expression in newborn CD4+ T cells PNAS, October 5, 2004; 101(40): 14473 - 14478. [Abstract] [Full Text] [PDF]
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K. A. Hagen, C. T. Moses, E. F. Drasler, K. M. Podetz-Pedersen, S. C. Jameson, and A. Khoruts A Role for CD28 in Lymphopenia-Induced Proliferation of CD4 T Cells J. Immunol., September 15, 2004; 173(6): 3909 - 3915. [Abstract] [Full Text] [PDF]
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J. Ehrchen, A. Sindrilaru, S. Grabbe, F. Schonlau, C. Schlesiger, C. Sorg, K. Scharffetter-Kochanek, and C. Sunderkotter Senescent BALB/c Mice Are Able To Develop Resistance to Leishmania major Infection Infect. Immun., September 1, 2004; 72(9): 5106 - 5114. [Abstract] [Full Text] [PDF]
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B. E. Anderson, J. M. McNiff, C. Matte, I. Athanasiadis, W. D. Shlomchik, and M. J. Shlomchik Recipient CD4+ T cells that survive irradiation regulate chronic graft-versus-host disease Blood, September 1, 2004; 104(5): 1565 - 1573. [Abstract] [Full Text] [PDF]
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U. Wagner, M. Pierer, M. Wahle, F. Moritz, S. Kaltenhauser, and H. Hantzschel Ex Vivo Homeostatic Proliferation of CD4+ T Cells in Rheumatoid Arthritis Is Dysregulated and Driven by Membrane-Anchored TNF{alpha} J. Immunol., August 15, 2004; 173(4): 2825 - 2833. [Abstract] [Full Text] [PDF]
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P. Hoffmann, R. Eder, L. A. Kunz-Schughart, R. Andreesen, and M. Edinger Large-scale in vitro expansion of polyclonal human CD4+CD25high regulatory T cells Blood, August 1, 2004; 104(3): 895 - 903. [Abstract] [Full Text] [PDF]
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B. Martin, A. Banz, B. Bienvenu, C. Cordier, N. Dautigny, C. Becourt, and B. Lucas Suppression of CD4+ T Lymphocyte Effector Functions by CD4+CD25+ Cells In Vivo J. Immunol., March 15, 2004; 172(6): 3391 - 3398. [Abstract] [Full Text] [PDF]
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P. Zhou, R. Borojevic, C. Streutker, D. Snider, H. Liang, and K. Croitoru Expression of Dual TCR on DO11.10 T Cells Allows for Ovalbumin-Induced Oral Tolerance to Prevent T Cell-Mediated Colitis Directed against Unrelated Enteric Bacterial Antigens J. Immunol., February 1, 2004; 172(3): 1515 - 1523. [Abstract] [Full Text] [PDF]
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B. Dubois, L. Chapat, A. Goubier, M. Papiernik, J.-F. Nicolas, and D. Kaiserlian Innate CD4+CD25+ regulatory T cells are required for oral tolerance and inhibition of CD8+ T cells mediating skin inflammation Blood, November 1, 2003; 102(9): 3295 - 3301. [Abstract] [Full Text] [PDF]
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J. Shimizu and E. Moriizumi CD4+CD25- T Cells in Aged Mice Are Hyporesponsive and Exhibit Suppressive Activity J. Immunol., February 15, 2003; 170(4): 1675 - 1682. [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. Aseffa, A. Gumy, P. Launois, H. R. MacDonald, J. A. Louis, and F. Tacchini-Cottier The Early IL-4 Response to Leishmania major and the Resulting Th2 Cell Maturation Steering Progressive Disease in BALB/c Mice Are Subject to the Control of Regulatory CD4+CD25+ T Cells J. Immunol., September 15, 2002; 169(6): 3232 - 3241. [Abstract] [Full Text] [PDF]
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M. C. Kullberg, D. Jankovic, P. L. Gorelick, P. Caspar, J. J. Letterio, A. W. Cheever, and A. Sher Bacteria-triggered CD4+ T Regulatory Cells Suppress Helicobacter hepaticus-induced Colitis J. Exp. Med., August 19, 2002; 196(4): 505 - 515. [Abstract] [Full Text] [PDF]
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P. Hoffmann, J. Ermann, M. Edinger, C. G. Fathman, and S. Strober Donor-type CD4+CD25+ Regulatory T Cells Suppress Lethal Acute Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation J. Exp. Med., August 5, 2002; 196(3): 389 - 399. [Abstract] [Full Text] [PDF]
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A. Banz, C. Pontoux, and M. Papiernik Modulation of Fas-Dependent Apoptosis: A Dynamic Process Controlling Both the Persistence and Death of CD4 Regulatory T Cells and Effector T Cells J. Immunol., July 15, 2002; 169(2): 750 - 757. [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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C. I. Kingsley, M. Karim, A. R. Bushell, and K. J. Wood CD25+CD4+ Regulatory T Cells Prevent Graft Rejection: CTLA-4- and IL-10-Dependent Immunoregulation of Alloresponses J. Immunol., February 1, 2002; 168(3): 1080 - 1086. [Abstract] [Full Text] [PDF]
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V. Malmstrom, D. Shipton, B. Singh, A. Al-Shamkhani, M. J. Puklavec, A. N. Barclay, and F. Powrie CD134L Expression on Dendritic Cells in the Mesenteric Lymph Nodes Drives Colitis in T Cell-Restored SCID Mice J. Immunol., June 1, 2001; 166(11): 6972 - 6981. [Abstract] [Full Text] [PDF]
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W. C. Kieper, M. Prlic, C. S. Schmidt, M. F. Mescher, and S. C. Jameson IL-12 Enhances CD8 T Cell Homeostatic Expansion J. Immunol., May 1, 2001; 166(9): 5515 - 5521. [Abstract] [Full Text] [PDF]
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Z. Trobonjaca, F. Leithauser, P. Moller, H. Bluethmann, Y. Koezuka, H. R. MacDonald, and J. Reimann MHC-II-Independent CD4+ T Cells Induce Colitis in Immunodeficient RAG-/- Hosts J. Immunol., March 15, 2001; 166(6): 3804 - 3812. [Abstract] [Full Text] [PDF]
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O. Annacker, R. Pimenta-Araujo, O. Burlen-Defranoux, T. C. Barbosa, A. Cumano, and A. Bandeira CD25+ CD4+ T Cells Regulate the Expansion of Peripheral CD4 T Cells Through the Production of IL-10 J. Immunol., March 1, 2001; 166(5): 3008 - 3018. [Abstract] [Full Text] [PDF]
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