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* Department of Immunology and Bacteriology, University of Glasgow, Glasgow, Scotland, United Kingdom; and Department of Immunology, University of Strathclyde, Glasgow, Glasgow, Scotland, United Kingdom
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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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We have investigated the role of CD4+CD25+ T cells in the development and function of Th1 and Th2 cells. We also extended this study to examine the role of CD4+CD25+ T cells in cutaneous Leishmania major infection in mice, a prototypic Th1/Th2 polarization model in vivo. Here we report that CD4+CD25+ T cells suppressed the differentiation and functions of both Th1 and Th2 cells. Furthermore, CD4+CD25+ T cells inhibited disease development of L. major infection in SCID mice reconstituted with CD24+CD25- T cells by suppressing both Th1 and Th2 cells development in vivo. We also showed that the SCID mice reconstituted with Th1 or Th2 cells differentiated from CD4+CD25- T cells developed spontaneous colitis, which was prevented by the cotransfer of CD4+CD25+ T cells. These results therefore provide direct evidence that CD4+CD25+ T cells play an important role in infection. These data may have implications in therapeutic strategy against infection and autoimmune diseases.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c mice and SCID mice (C.B-17) of the BALB/c background were obtained from Harlan Olac (Bicester, U.K.). All mice were kept at the Biological Service facilities of University of Glasgow and University of Strathclyde according to the U.K. Home Office guidelines. Mice, both male and female, were used at 6–10 wk of age. SCID mice were infected in the right hind footpad with 1 x 106 stationary phase Leishmania major (LV39) promastigotes 1 day after receiving i.p. 5 x 105 CD4+CD25-, CD4+CD25+ or a combination of the two cell populations. Lesion development was followed by measuring footpad swelling (the difference between the infected and the uninfected footpad) at regular intervals. The maintenance of parasite, infection, and measurement of disease progression were described previously (8). At the end of the experiment mice were sacrificed, and footpads were removed to assay for parasite load by limiting dilution (8). Draining lymph node cells were harvested and cultured (2 x 106 cells/ml in culture medium) in vitro with frozen-thawed parasite Ag (106 parasite/ml equivalent). Culture supernatant was harvested at 72 h and assayed for cytokines by ELISA. Cellular proliferation was also determined by [3H]thymidine incorporation (8). The colons of the mice were also collected and fixed with formalin for histological analysis.
Cell culture
CD4+ T cells were purified from BALB/c lymph nodes by negative selection using magnetic beads (MACS; Miltenyi Biotech, Auburn, CA) as described previously (9). CD4+ cells were then further separated into CD25+ and CD25- populations by MACS and FACS sorter (FACSCalibur; BD Biosciences, Mountain View, CA) using PE-labeled anti-CD25 Ab (BD Biosciences). The purity of the cell preparations was determined by FACS analysis and was routinely >95%. In some experiments CD4+CD25- T cells were cultured with soluble anti-CD3 Ab (1 µg/ml; BD PharMingen, San Diego, CA) and mitomycin C-treated BALB/c spleen cells (APC) for 3 days with or without an equal number of CD4+CD25+ T cells. Cellular proliferation and type 1 and type 2 cytokine production were analyzed by [3H]thymidine incorporation and ELISA, respectively. In some experiments CD4+CD25- and CD4+CD25+ cells were cultured in a 96-well plate together or separated by a semipermeable membrane (Transwell; Millipore, Watford, U.K.). In other experiments CD4+CD25- T cells were cultured with anti-CD3 Ab, anti-CD28 (1 µg/ml; BD PharMingen), and IL-12 (10 ng/ml; Genetics Institute, Cambridge, MA) plus anti-IL-4 Ab (1 µg/ml) for Th1 cell induction, or IL-4 (10 ng/ml) plus anti-IL-12 Ab (1 µg/ml) for Th2 cell induction (all reagents from R&D Systems, Oxon, U.K.). At the end of 3-day culture, the cells were harvested, rested for 3 days in medium containing IL-2 (10 ng/ml; BD PharMingen), and recultured as described above. After two cycles of culture, the cells were phenotyped for Th1 or Th2 by cytokine secretion and CD44 and CD62L expression. Greater than 95% of the cells were CD44+CD62L- and produced the expected cytokines. They were adoptively transferred i.p. into SCID mice either alone or with equal numbers of freshly collected CD4+CD25+ T cells. Colitis development was then monitored by body weight and histological analysis at the end of the experiments.
CFSE analysis
CD4+CD25- and CD4+CD25+ T cells were labeled with CFSE (Molecular Probes, Eugene, OR) according to the manufacturer’s instruction. The labeled cells were cultured for 3 days as described above and were analyzed by FACS.
ELISA and Ab titration
Cytokine concentrations were determined by ELISA, using paired
Abs (BD PharMingen). Detection limits were: IL-4 and IL-5, 30 pg/ml;
and IL-2 and IFN-
, 40 pg/ml. Anti-leishmanial Ab titers in the
pooled sera (n = 5) were detected with
biotin-conjugated anti-mouse IgG or IgG2a (BD PharMingen), followed
by conjugated avidin peroxidase (Sigma-Aldrich, St. Louis, MO) with
tetramethylbenzidine substrate (Kirkegaard & Perry, Gaithersburg,
MD).
Histological examination
Colons were removed from mice 4–8 wk after T cell reconstitution and were fixed in 10% buffered formalin. Paraffin-embedded sections (6 µm) were cut and stained with H&E. Inflammation was scored as previously described (10). The sections were scanned with a Duoscan T2000XL microscope, and pictures were taken with a Fuji X digital camera (HC-300Z; Tokyo, Japan) at magnification of x15 or x200.
Statistical analysis
Statistics were determined using Mintab software for Macintosh (Cupertino, CA). The analyses were performed using Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD4+ T cells were purified from the lymph
nodes of BALB/c mice by negative selection and then sorted into
CD25+ or CD25- T cells.
CD4+CD25- T cells were
cultured alone or together with
CD4+CD25+ T cells in the
presence of soluble anti-CD3 Ab- and mitomycin C-treated spleen
cells (APC providing costimulating signals). The cells were driven to
Th1 or Th2 lineages by culture for 3 days with IL-12 plus anti-IL-4
Ab or IL-4 plus anti-IL-12 Ab, respectively. Cellular proliferation
and cytokine production patterns were analyzed on day 3 of culture. In
the absence of exogenously added cytokines,
CD4+CD25- T cells produced
significant proliferation (stimulation index, 15–20), whereas
CD4+CD25+ cells did not
(data now shown).
CD4+CD25- T cells
differentiated into Th1 and Th2 cells as expected in the presence of
IL-12 and IL-4, respectively (Fig. 1
).
Under these culture conditions,
CD4+CD25+ T cells alone did
not produce significant amount of IFN-, IL-4, or IL-5. However, the
induction of both Th1 and Th2 cells from
CD4+CD25- cells was
suppressed when they were cultured together with
CD4+CD25+ cells (Fig. 1a). It should be noted that
CD4+CD25+ T cells alone,
under these culture conditions, did not proliferate when cultured with
IL-12, but proliferated significantly in the presence of IL-4. However,
when cultured together in the presence of IL-4, the proliferation of
both CD4+CD25- and
CD4+CD25+ cells were
significantly diminished compared with the proliferation when the two
populations of cells were cultured separately. Nevertheless, such
proliferation of CD4+CD25+
T cells in the presence of IL-4 did not affect their ability to
suppress the development of functional activity of Th2 cells from
CD4+CD25- T cells (i.e.,
the production of type 2 cytokines; Fig. 1b). CFSE analysis
(Fig. 2a) supports the
cellular proliferation profile shown in Fig. 1a.
CD4+CD25- cells
proliferated equally well in the presence or the absence of IL-4. In
contrast, CD4+CD25+ cells
proliferated poorly in the absence of IL-4. When cultured with
CD4+CD25+ T cells,
CD4+CD25- cells showed
markedly reduced proliferation compared with that when cells were
cultured without CD4+CD25+
cells. This was particularly so in the absence of IL-4. When cultured
with CD4+CD25- T cells,
CD4+CD25+ cells also showed
significantly reduced proliferation compared with that when cells were
cultured alone, even in the presence of IL-4. The percentages of dead
cells after 3-day culture were similar in all cultures (20–25%). The
suppression mediated by
CD4+CD25+ cells required
cell contact between the
CD4+CD25+ cells and
CD4+CD25- cells, because
no suppression was detected when these two cell populations were
cultured in Transwells separated by a semipermeable membrane (Fig. 2b).
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We next investigated whether the suppression of Th1 and Th2 cell
development in vitro was also manifested in vivo. Cutaneous
leishmaniasis in mice provides the most polarized form of Th1 and Th2
dichotomy in vivo. We therefore examined the effect of
CD4+CD25+ T cells on
CD4+CD25- cells in a SCID
mouse model of L. major infection. This study would also
provide definitive information on the hitherto unknown effect of
CD4+CD25+ Treg cells on
infectious disease. Initially, we investigated the physiological role
of CD4+CD25+ T cells on the
development of L. major infection. SCID mice were adoptively
transferred i.p. with 5 x 105 BALB/c spleen
cells, depleted or undepleted of
CD4+CD25+ T cells, which
constitute 
5% of the CD4+ T cell population
in the spleen. The recipients were infected 1 day later with 1 x
106 L. major promastigotes in the
footpads, and lesion development was followed at regular intervals. As
expected, SCID mice did not develop local lesions over the 4-wk period
after infection because the local inflammation was
CD4+ T cell dependent (11). SCID
mice reconstituted with the whole spleen cell population developed
significant and progressive lesions. Interestingly, mice reconstituted
with spleen cells depleted of
CD4+CD25+ T cells developed
even more severe lesions and higher parasite load (Fig. 3a). This pattern of disease
development persisted for at least 60 days (data not shown), at which
stage the experiments were terminated as required by the Home Office
guidelines. These data therefore demonstrated that in the present
experimental model,
CD4+CD25+ T cells
suppressed lesion development as well as parasite multiplication in
SCID mice adoptively transferred with a low dose of BALB/c spleen
cells. To analyze the immune mechanisms involved, some groups of mice
were sacrificed on day 28 postinfection, and their lymphoid cells were
cultured with leishmanial Ags in vitro. Cells from mice reconstituted
with CD4+CD25+ T
cell-depleted spleen cells produced significantly more IFN- and IL-4
than cells from mice reconstituted with the intact spleen cells (Fig. 3b). Furthermore, mice reconstituted with
CD4+CD25+ T cell-depleted
spleen cells produced substantially elevated levels of
leishmanial-specific IgG1 and IgG2a Abs compared with mice
reconstituted with the intact spleen cells (Fig. 3c).
Importantly, SCID mice reconstituted with
CD4+CD25+ T cell-depleted
spleen cells developed severe colitis, whereas mice reconstituted with
intact spleen cells or control unreconstituted mice did not (Fig. 3d). Mice that developed colitis began to lose weight and
had diarrhea from wk 4 post-cell transfer (data not shown). These data
therefore demonstrate that
CD4+CD25+ T cells play an
important role in suppressing T and B cell functions and controlling
leishmanial infection and colitis.
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a). This was accompanied by
suppression of both IFN- and IL-4 production in these mice (Fig. 4b). Furthermore, SCID mice reconstituted with
CD4+CD25- T cells, but not
CD4+CD25+ T cells,
developed severe colitis. The disease induced by
CD4+CD25- T cells was
completely abrogated by cotransfer with
CD4+CD25+ T cells (data not
shown). These data therefore demonstrate directly that
CD4+CD25-, but not
CD4+CD25+, T cells from
BALB/c mice mediated exacerbated leishmanial infection and induced
rapid colitis in the infected mice. Furthermore,
CD4+CD25+ T cells
effectively inhibited the disease-promoting activity of
CD4+CD25- T cells.
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We have demonstrated the suppressive effect of
CD4+CD25+ T cells on the
differentiation of Th1 and Th2 cells from naive
CD4+CD25- T cells. We next
investigated whether
CD4+CD25+ T cells are able
to regulate committed Th1 and Th2 cells. The results from this study
could have important implications for the therapeutic potential of
CD4+CD25+ T cells in
infection and inflammatory diseases. Since
CD4+CD25- cells induced
spontaneous colitis in SCID mice (Figs. 3
and 4), and it has been
recently demonstrated that both Th1 and Th2 are able to induce colitis
in SCID mice (12), we used a modified version of this
convenient model for further investigation. This model also avoided the
added complexity of infection.
CD4+CD25- T cells from
BALB/c spleens were driven to Th1 or Th2 lineages by culture with
anti-CD3 and anti-CD28 in the presence of IL-12 and
anti-IL-4 Ab, or IL-4 and anti-IL-12 Ab, respectively. After
two rounds of culture, >95% of the cells were
CD44+CD62L-, a phenotype
of mature T cells. The Th1 line produced IFN- (90.3 ng/ml) and no
detectable IL-5, and the Th2 line produced IL-5 (39.1 ng/ml) and no
detectable IFN-. The cells were injected i.p. (5 x
105 cells/recipient) to SCID mice with or without
an equal number of
CD4+CD25+ T cells from
syngenic donors. The body weights of mice were monitored at regular
intervals, and the animals were sacrificed 8 wk after cell transfer.
Mice receiving CD4+CD25+ T
cells developed normal body weight gain. In contrast, SCID mice given
Th1 or Th2 cells failed to gain body weight from the onset of cell
transfer and began to lose weight from wk 6. The body weight profile
was similar for the Th1 and Th2 recipients. Crucially, the weight loss
induced by Th1 or Th2 cells was prevented by cotransfer with
CD4+CD25+ T cells (Fig. 5a). This was particularly
evident in the recipients of Th2 cells, in which the reversal was
apparent from wk 1 of the cell transfer. For Th1 cells this was not
achieved until wk 6. At the end of the experiments (wk 8), mesenteric
lymph node cells were harvested and cultured with anti-CD3 Ab, and
the cytokines produced were determined. Mice receiving Th1 or Th2 cells
alone retained much of the type 1 or type 2 cytokine profile,
respectively. Cytokine synthesis was completely suppressed by the
cotransfer with CD4+CD25+ T
cells (Fig. 5b). Histological analysis of colonic tissues at
wk 8 showed that the recipients of both Th1 and Th2 cells developed
typical colitis pathology, which was completely reversed by
CD4+CD25+ T cells (Fig. 5c). These results therefore demonstrate that 1) both Th1
and Th2 cells derived from
CD4+CD25- T cells can
induce spontaneous colitis in SCID mice; 2)
CD4+CD25+ T cells can
suppress the functions of committed Th1 and Th2 cells; and 3) the
suppressive effect of
CD4+CD25+ T cells on Th2
cells appears to be more profound than that on Th1 cells in this
model.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cutaneous leishmaniasis is arguably the most clear-cut example of Th1 and Th2 cell polarization in vivo. The outcome of infection is determined by the balance of Th1 and Th2 cell functions. Early studies suggested a greater heterogeneity of CD4+ T cells beyond the current Th1/Th2 categorization (13). In leishmaniasis, the immune response and outcome of infection may well be influenced by the presence and activation of other T cell types, including Treg cells. In 1983, a line of CD4+ suppressor T cells was cloned from BALB/c mice with progressive L. major infection and was shown to suppress Ag-specific T cell proliferation and delayed-type hypersensitivity (14). The phenotype of these suppressor T cells was not fully characterized, but could well be the CD4+CD25+ Treg cells described here. The data reported here are the first demonstration of the regulatory role of CD4+CD25+ T cells in parasitic infection and may have wider implications in infectious diseases in general. The suppressive activity of the CD4+CD25+ T cells described here is distinct from that of the Ag-specific, IL-10-producing Tr1 cells induced during infection in mice and humans (15, 16, 17). No elevated IL-10 level was detected in the mice transferred with CD4+CD25+ T cells in our system (data not shown).
The CD4+CD25+ T cells reported here suppressed proliferation and cytokine production by both Th1 and Th2 cells in vitro and in vivo. This finding is in apparent contrast to early reports showing that, using T cells from OVA peptide-specific TCR-transgenic mice, CD4+CD25+ T cell depletion led to the preferential enhancement of Th1 cells development in vitro (18, 19). The discrepancy between this and our system may be due to the difference in cell type used (i.e., TCR vs polyclonal T cells). This may lead to a difference in the threshold of suppression between Th1 and Th2 cells. A more likely explanation, however, may be the difference in the experimental systems used. Once activated, CD4+CD25+ T cells are not Ag specific in their suppression and are likely to be nondiscriminatory against proliferating T cells, including CD8+ T cells (20). In the OVA TCR-transgenic system, T cells were selectively driven to the Th2 pathway in a Th2 cell-mediated airway allergic model and may thus be selectively suppressed.
Cutaneous leishmanial infection in SCID mice is critically dependent on
the presence of CD4+ T cells (11)
and the dose of cells adoptively transferred (21, 22, 23).
Reconstitution of SCID mice with 107 naive BALB/c
spleen cells led to resistance against L. major infection,
whereas transfer of 108 of such cells rendered
the mice highly susceptible to the infection. Using a low dose of cells
(5 x 105 cells/recipient), we have shown
here that the disease development in our SCID/cell transfer model, at
least during the initial 8 wk, was dependent on the presence of
CD4+CD25-, but not
CD4+CD25+, T cells.
CD4+CD25- T cells from the
susceptible BALB/c mice developed into both Th1 and Th2 cells following
leishmanial infection, with a dominant, but not exclusive, Th2 response
and the development of progressive lesions.
CD4+CD25+ T cells
suppressed the differentiation of
CD4+CD25- T cells to both
Th1 and Th2 cells and the suppression of disease development. There may
be a number of interpretations for this disease outcome. 1) Th2 cells
appeared to be more susceptible to the inhibitory effect of
CD4+CD25+ T cells. This
shift of balance in favor of Th1 cells may account for the enhanced
resistance to the infection by the cotransfer of
CD4+CD25+ Treg cells. The
higher degree of sensitivity of Th2 cells compared with Th1 cells to
the suppression of
CD4+CD25+ T cells in vivo
was also apparent in the colitis induced by Th1 and Th2 cells (Fig. 5).
However, the different culture conditions used to drive Th1 and Th2
cells precluded a direct comparison of the relative sensitivity of
these cells to the suppressive effect of
CD4+CD25+ T cells in vitro.
2) An early burst of IL-4 has been shown to favor the subsequent
development of Th2 cells in BALB/c mice infected with L.
major (24). It is possible that
CD4+CD25+ cells
preferentially inhibited such an early event. 3) It is also possible
that in BALB/c mice the determining factor in the outcome of the
disease is the level of IL-4 rather than the presence of IFN-. Thus,
the suppression of IL-4 would lead to enhanced resistance even with the
concomitant decrease in IFN-. Whatever the explanation, it appears
that CD4+CD25+ T
cells are important for host resistance against cutaneous leishmanial
infection in the highly susceptible BALB/c mice.
An earlier study using a high infecting dose of L. major
(25), showed that SCID mice adoptively transferred with
leishmanial-specific, IL-4-producing
CD4+CD45RBlow cells
developed nonhealing lesions, whereas mice transferred with
leishmanial-primed, IFN-producing,
CD4+CD45RBhigh cells
produced a healing response. Furthermore, mice reconstituted with
CD4+CD45RBhigh cells
developed severe colitis, which could be inhibited by the cotransfer
with CD4+CD45RBlow cells.
It is unlikely that the effect of
CD4+CD25+ cells we observed
here with the Leishmania infection was due to a low grade
contamination with
CD4+CD45RBhigh cells. In
this early study
CD4+CD45high cells were
from a highly primed leishmanial-specific cell population. Naive cells
were not effective in the enhancement of disease development.
Furthermore, CD4+CD45RBhigh
cells induced spontaneous colitis in SCID mice. The
CD4+CD25+ cells reported
here were freshly isolated, leishmanial-naive T cells, which did not
produce IFN- in vivo and, importantly, prevented colitis induction
by CD4+CD25- cells. Thus,
the CD4+CD25+ cells used
here were more akin to the
CD4+CD45RBlow cells, which
would be expected to counteract any small amount of contaminating
CD4+CD45high cells.
However, the relationship between
CD4+CD25+ and
CD4+CD45RBlow Treg cells is
currently unclear.
CD4+CD45RBlow cells
prevent colitis by IL-10 and TGF-
(10). The
CD4+CD25+ T cells described
here did not produce appreciable level of cytokines and performed their
functions by cell contact. It will be of considerable interest to know
whether CD4+CD45RBlow
cells represent a subset of
CD4+CD25+ regulatory T
cells or belong to a distinct lineage. Contrary to earlier reports,
recent investigations now show that both Th1 and Th2 cells are
pathogenic in an Ag-specific model of colitis (12). In our
non-Ag-specific model, colitis was induced by established Th1 and Th2
cell lines with similar kinetics and severity. Importantly, our results
provide direct in vivo documentation that
CD4+CD25+ T cells
suppressed both Th1 and Th2 cells, resulting in the resolution of
colitis. This finding strongly suggests that
CD4+CD25+ T cells may have
important therapeutic potential. This is supported by an early report
(26) that in a murine gastritis model, an Ag-specific Th1
and a Th2 cell line could adoptively transfer the disease in
nu/nu mice, and that the disease could be prevented by
cotransfer of normal spleen cells, which presumably contained
CD4+CD25+ T cells.
In summary, we demonstrate here that CD4+CD25+ regulatory T cells effectively suppress the induction and functions of Th1 and Th2 cells crucial to the outcome of infectious and inflammatory diseases. This finding strongly suggests that CD4+CD25+ T cells could play an important therapeutic role in Th1 and Th2 cell-mediated diseases.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Foo Y. Liew or Dr. Damo Xu, Department of Immunology and Bacteriology, University of Glasgow, Glasgow, Scotland, U.K. G11 6NT. E-mail addresses: fyl1h@clinmed.gla.ac.uk or d.xu{at}clinmed.gla.ac.uk
3 Abbreviation used in this paper: Treg, regulatory T.
Received for publication July 8, 2002. Accepted for publication October 23, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155:1151.[Abstract]
but not by a T(h)1 to T(h)2 shift. Int. Immunol. 12:623.4 V8 CD4+ T cells instructs Th2 development and susceptibility to Leishmania major in BALB/c mice. Immunity 6:541.[Medline]
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 H. Liu, M. Komai-Koma, D. Xu, and F. Y. Liew Toll-like receptor 2 signaling modulates the functions of CD4+CD25+ regulatory T cells PNAS, May 2, 2006; 103(18): 7048 - 7053. [Abstract] [Full Text] [PDF]
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M. Baumgart, F. Tompkins, J. Leng, and M. Hesse Naturally Occurring CD4+Foxp3+ Regulatory T Cells Are an Essential, IL-10-Independent Part of the Immunoregulatory Network in Schistosoma mansoni Egg-Induced Inflammation J. Immunol., May 1, 2006; 176(9): 5374 - 5387. [Abstract] [Full Text] [PDF]
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C.-C. Chen, S. Louie, B. A. McCormick, W. A. Walker, and H. N. Shi Helminth-Primed Dendritic Cells Alter the Host Response to Enteric Bacterial Infection J. Immunol., January 1, 2006; 176(1): 472 - 483. [Abstract] [Full Text] [PDF]
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J. Kearley, J. E. Barker, D. S. Robinson, and C. M. Lloyd Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent J. Exp. Med., December 5, 2005; 202(11): 1539 - 1547. [Abstract] [Full Text] [PDF]
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 T. L. Guo, R. P. Chi, D. R. Germolec, and K. L. White Jr. Stimulation of the Immune Response in B6C3F1 Mice by Genistein Is Affected by Exposure Duration, Gender, and Litter Order J. Nutr., October 1, 2005; 135(10): 2449 - 2456. [Abstract] [Full Text] [PDF]
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 S. P Hickman and L. A Turka Homeostatic T cell proliferation as a barrier to T cell tolerance Phil Trans R Soc B, September 29, 2005; 360(1461): 1713 - 1721. [Abstract] [Full Text] [PDF]
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A. Kariminia, E. Bourreau, H. Pascalis, P. Couppie, D. Sainte-Marie, F. Tacchini-Cottier, and P. Launois Transforming Growth Factor {beta}1 Production by CD4+ CD25+ Regulatory T Cells in Peripheral Blood Mononuclear Cells from Healthy Subjects Stimulated with Leishmania guyanensis Infect. Immun., September 1, 2005; 73(9): 5908 - 5914. [Abstract] [Full Text] [PDF]
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C. B. Stober, U. G. Lange, M. T. M. Roberts, A. Alcami, and J. M. Blackwell IL-10 from Regulatory T Cells Determines Vaccine Efficacy in Murine Leishmania major Infection J. Immunol., August 15, 2005; 175(4): 2517 - 2524. [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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 D. T. Nardelli, J. P. Cloute, K. H. K. Luk, J. Torrealba, T. F. Warner, S. M. Callister, and R. F. Schell CD4+ CD25+ T Cells Prevent Arthritis Associated with Borrelia Vaccination and Infection Clin. Vaccine Immunol., June 1, 2005; 12(6): 786 - 792. [Abstract] [Full Text] [PDF]
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Y. Chung, S.-H. Lee, D.-H. Kim, and C.-Y. Kang Complementary role of CD4+CD25+ regulatory T cells and TGF-{beta} in oral tolerance J. Leukoc. Biol., June 1, 2005; 77(6): 906 - 913. [Abstract] [Full Text] [PDF]
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J. Ji, J. Masterson, J. Sun, and L. Soong CD4+CD25+ Regulatory T Cells Restrain Pathogenic Responses during Leishmania amazonensis Infection J. Immunol., June 1, 2005; 174(11): 7147 - 7153. [Abstract] [Full Text] [PDF]
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I. Suffia*, S. K. Reckling*, G. Salay*, and Y. Belkaid* A Role for CD103 in the Retention of CD4+CD25+ Treg and Control of Leishmania major Infection J. Immunol., May 1, 2005; 174(9): 5444 - 5455. [Abstract] [Full Text] [PDF]
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J. S. Satoguina, E. Weyand, J. Larbi, and A. Hoerauf T Regulatory-1 Cells Induce IgG4 Production by B Cells: Role of IL-10 J. Immunol., April 15, 2005; 174(8): 4718 - 4726. [Abstract] [Full Text] [PDF]
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 D. Lundsgaard, T. L. Holm, L. Hornum, and H. Markholst In Vivo Control of Diabetogenic T-Cells by Regulatory CD4+CD25+ T-Cells Expressing Foxp3 Diabetes, April 1, 2005; 54(4): 1040 - 1047. [Abstract] [Full Text] [PDF]
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P. E. Rao, A. L. Petrone, and P. D. Ponath Differentiation and Expansion of T Cells with Regulatory Function from Human Peripheral Lymphocytes by Stimulation in the Presence of TGF-{beta} J. Immunol., February 1, 2005; 174(3): 1446 - 1455. [Abstract] [Full Text] [PDF]
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Z. Liu and L. Lefrancois Intestinal Epithelial Antigen Induces Mucosal CD8 T Cell Tolerance, Activation, and Inflammatory Response J. Immunol., October 1, 2004; 173(7): 4324 - 4330. [Abstract] [Full Text] [PDF]
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B. T. Rouse and S. Suvas Regulatory Cells and Infectious Agents: Detentes Cordiale and Contraire J. Immunol., August 15, 2004; 173(4): 2211 - 2215. [Abstract] [Full Text] [PDF]
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A. L. Kinter, M. Hennessey, A. Bell, S. Kern, Y. Lin, M. Daucher, M. Planta, M. McGlaughlin, R. Jackson, S. F. Ziegler, et al. CD25+CD4+ Regulatory T Cells from the Peripheral Blood of Asymptomatic HIV-infected Individuals Regulate CD4+ and CD8+ HIV-specific T Cell Immune Responses In Vitro and Are Associated with Favorable Clinical Markers of Disease Status J. Exp. Med., August 2, 2004; 200(3): 331 - 343. [Abstract] [Full Text] [PDF]
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S. Mendez, S. K. Reckling, C. A. Piccirillo, D. Sacks, and Y. Belkaid Role for CD4+ CD25+ Regulatory T Cells in Reactivation of Persistent Leishmaniasis and Control of Concomitant Immunity J. Exp. Med., July 19, 2004; 200(2): 201 - 210. [Abstract] [Full Text] [PDF]
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M. Stassen, H. Jonuleit, C. Muller, M. Klein, C. Richter, T. Bopp, S. Schmitt, and E. Schmitt Differential Regulatory Capacity of CD25+ T Regulatory Cells and Preactivated CD25+ T Regulatory Cells on Development, Functional Activation, and Proliferation of Th2 Cells J. Immunol., July 1, 2004; 173(1): 267 - 274. [Abstract] [Full Text] [PDF]
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B. K. Choi, J. S. Bae, E. M. Choi, W. J. Kang, S. Sakaguchi, D. S. Vinay, and B. S. Kwon 4-1BB-dependent inhibition of immunosuppression by activated CD4+CD25+ T cells J. Leukoc. Biol., May 1, 2004; 75(5): 785 - 791. [Abstract] [Full Text] [PDF]
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Z. Jaffar, T. Sivakuru, and K. Roberts CD4+CD25+ T Cells Regulate Airway Eosinophilic Inflammation by Modulating the Th2 Cell Phenotype J. Immunol., March 15, 2004; 172(6): 3842 - 3849. [Abstract] [Full Text] [PDF]
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A. Cavani, F. Nasorri, C. Ottaviani, S. Sebastiani, O. De Pita, and G. Girolomoni Human CD25+ Regulatory T Cells Maintain Immune Tolerance to Nickel in Healthy, Nonallergic Individuals J. Immunol., December 1, 2003; 171(11): 5760 - 5768. [Abstract] [Full Text] [PDF]
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H. Liu, B. Hu, D. Xu, and F. Y. Liew CD4+CD25+ Regulatory T Cells Cure Murine Colitis: The Role of IL-10, TGF-{beta}, and CTLA4 J. Immunol., November 15, 2003; 171(10): 5012 - 5017. [Abstract] [Full Text] [PDF]
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S. Suvas, U. Kumaraguru, C. D. Pack, S. Lee, and B. T. Rouse CD4+CD25+ T Cells Regulate Virus-specific Primary and Memory CD8+ T Cell Responses J. Exp. Med., September 15, 2003; 198(6): 889 - 901. [Abstract] [Full Text] [PDF]
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S. Sakaguchi Control of Immune Responses by Naturally Arising CD4+ Regulatory T Cells That Express Toll-like Receptors J. Exp. Med., February 17, 2003; 197(4): 397 - 401. [Full Text] [PDF]
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