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, and CTLA41
Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Ab. However, the resurgence of colitis under these treatments was not accompanied by the reactivation of Th1 or Th2 response nor was it correlated to the parasite load. These results therefore demonstrate that CD4+CD25+ T cells are therapeutic and that the effect is mediated by both IL-10/TGF--dependent and independent mechanisms. Furthermore, colitis can manifest independent of Th1 and Th2 responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have investigated the role of CD4+CD25+ T cells in regulating the development of inflammatory colitis, a common pathology of inflammatory bowel disease (IBD) that affects 1 of 1000 people in the western world. The colitis model used in this study is induced by the effector CD4+CD25- T cells in SCID mice. The disease could be considerably accelerated by concomitant s.c. infection of the recipients with the protozoan parasite Leishmania major. The colitis developed about 1 wk after cell transfer, and the disease could be completely reversed and normal health restored by transferring CD4+CD25+ T cells even up to 21 days after the disease onset. Furthermore, the curative activity of the Treg cells was completely abolished by anti-IL-10R, anti-CTLA4, or anti-TGF- Ab. These results therefore demonstrate directly that CD4+CD25+ Treg cells have therapeutic potential against an established inflammatory disease and that IL-10, CTLA4, and TGF- are closely involved in the suppressive effect in vivo.
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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, Oxon, U.K.). All mice were kept in the Biological Service facilities in the University of Glasgow according to the U.K. Home Office guidelines. Both male and female mice were used at 6–10 wk of age. SCID mice were injected i.p. with (5 x 105 cells per mouse) CD4+CD25- cells, CD4+CD25+ cells, or a combination (equal number) of the two cell populations. One day later, the animals were infected in the right hind footpad with 1 x 106 stationary phase L. major (LV39) promastigotes. The maintenance of parasite, infection, and measurement of disease progression were described previously (8). To induce experimental colitis, SCID mice were reconstituted i.p. with freshly isolated CD4+CD25- T cells with or without Leishmania infection. To test the therapeutic effect of CD4+CD25+ T cells, colitis was established in SCID mice, as described above, and then injected i.p. with 5 x 105 freshly isolated or activated CD4+CD25+ T cells at various times after the transfer of CD4+CD25- T cells. In some experiments, the recipient mice were also treated with specific Abs. Anti-IL-10R Ab (kindly provided by K. Moore, DNAX, Palo Alto, CA; 1 mg/mouse/injection) was injected weekly, anti-CTLA4 (clone UC10-4F10-11; American Type Culture Collection (ATCC), Manassas, VA; 0.25 mg/mouse/injection) was given twice per week, or anti-TGF- Ab (clone 1D11.16; ATCC; 1 mg/mouse/injection) was injected weekly. All Abs were injected i.p. for 3 wk in mice transferred with CD4+CD25+ and/or CD4+CD25- T cells on the day of cell transfer. Control mice were injected with normal rat IgG (1 mg/mouse/injection; Sigma-Aldrich, Poole, U.K.). All mice were monitored closely for body weight change and for general health status, according to the U.K. Home Office guidelines for animal experimentation. Experiments were terminated when the mice developed severe diarrhea and were incontinent or lost up to 20% of their initial body weight. At the end of the experiments, mice were sacrificed and mesenteric lymph nodes were harvested and cultured (2.5 x 105 cells/ml in culture medium) in vitro with plate-bound anti-CD3 Ab (5 µg/ml; BD PharMingen, Oxford, U.K.). Culture supernatant was harvested at 72 h and assayed for cytokines by ELISA, using paired Abs (BD PharMingen). Detection limits were: IL-4, 5 pg/ml; IFN-
, 40 pg/ml. Cellular proliferation was also determined by [3H]thymidine incorporation. Colons of the mice were also collected and fixed for histological analysis.
Cell culture
CD4+ T cells were purified from BALB/c lymph nodes by negative selection (9) using CD4+ isolation kit (MACS; Miltenyi Biotec, Auburn, CA). CD4+ cells were then further separated into CD25+ and CD25- populations by MACS and FACS sorter (FACSCalibur; BD Biosciences, San Jose, CA) using PE-labeled anti-CD25 Ab (BD PharMingen) and anti-PE Ab conjugated with Microbeads (Miltenyi Biotec). The purity of the cell preparations was determined by FACS analysis and was routinely >95%. In some experiments, CD25+ T cells were activated with plate-bound anti-CD3 (5 µg/ml) Ab, anti-CD28 (1 µg/ml) Ab, and IL-2 (10 ng/ml) with or without TGF- (1 ng/ml) for 3 days. The activated cells were then rested in the presence of 10 ng/ml of IL-2 for another 3 days before being washed and transferred into recipient mice.
Histological examination
Colons were removed from mice at different times after T cell reconstitution and fixed in 10% buffered Formalin. Paraffin-embedded sections (6 µm) were cut and stained with H&E. Inflammation was scored, as described previously (10). Each sample was graded from a scale of 0–4: 0 = normal; 1 = mild epithelial hyperplasia; 2 = pronounced hyperplasia and significant inflammatory infiltrates; 3 = severe hyperplasia and infiltration with significant decrease in goblet cells; 4 = severe hyperplasia, severe transmural inflammation, ulceration, crypt abscesses, and substantial depletion of goblet cells. Ceca and colons were assessed separately, and at least three separate sections from each sample were scored blind. The sections were scanned with a Duoscan T2000XL microscope, and pictures were taken with a Fuji X digital camera (HC-300Z) at a magnification of x100.
Statistical analysis
Statistics were performed using Mintab software for the Macintosh. The analyses were performed using Student’s t test.
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Results |
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We first established a mouse colitis model that is amenable to the modulatory effect of CD4+CD25+ T cells. In a recent report (11), we showed that SCID mice adoptively transferred with spleen cells depleted of CD4+CD25+ T cells developed severe colitis following s.c. infection with the protozoan parasite, Leishmania major. We therefore first defined the cell types and the conditions leading to the colitis, which will serve as a model for inflammatory disease in vivo. CD4+CD25+ and CD4+CD25- T cells were purified from the spleen and lymph nodes of naive BALB/c mice and then adoptively transferred to SCID mice (C.B-17) of the BALB/c background. Some of the recipients were infected with L. major in the footpad 1 day after the cell transfer. Colitis development was followed for the next 8 wk. SCID mice transferred with CD4+CD25+ T cells did not develop any sign of colitis, with normal body weight gain with or without L. major infection (Fig. 1). In contrast, SCID recipients of CD4+CD25- T cells developed IBD. This was particularly severe in mice with concomitant L. major infection, exhibiting loose stools and marked weight loss 2 wk after cell transfer and showing clear colonic enlargement with pronounced epithelial hyperplasia by 3 wk after cell transfer (Fig. 1, b and c). It should also be noted that SCID mice adoptively transferred with CD4+CD25- T cells and infected with L. major developed significant footpad lesions that peaked at 3 wk, but progressively declined and reached a low, but steady level by 7 wk after infection (Fig. 1d). In contrast, L. major-infected SCID mice injected with CD4+CD25+ T cells did not develop significant footpad lesions until 4 wk after infection, but the lesions progressed inexorably by 8 wk after infection (Fig. 1d). The footpad lesion size is directly correlated to the parasite load in the footpad (data not shown). By wk 8 of infection, the parasite load of the mice transferred with CD4+CD25+ cells was 6.5 log10, while that of mice transferred with CD4+CD25- cells was 2.0 log10. This pattern of infection development is in apparent contrast to the disease progression reported earlier (11). However, in this earlier report, the lesions were measured up to only 27 days after L. major infection, and this disease pattern was reproduced in the present report. The disease development in this model at the later stages was similar to that reported by Belkaid et al. (12). These results show that naive CD4+CD25- T cells can induce spontaneous colitis in SCID mice and that the disease could be markedly accelerated by Leishmania infection. We therefore decided to use this severe colitis model to investigate the therapeutic potential of CD4+CD25+ regulatory T cells on inflammatory disease.
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CD4+CD25+ T cells were purified from naive BALB/c mice and were used freshly isolated or cultured with plate-bound anti-CD3 Ab (activated) with or without TGF-. The cells were then washed, rested, and injected i.p. into SCID mice that had received similar number of naive CD4+CD25- T cells and were infected with L. major 10 or 21 days previously. Mice receiving CD4+CD25- T cells alone developed severe colitis by 21 days, with a clear onset of disease by 10 days after cell transfer. This was clearly demonstrated by body weight loss and colon pathology (Fig. 2b). Remarkably, SCID mice given the CD4+CD25- T cells and then injected with CD4+CD25+ T cells, as late as day 10 and even day 21 after the first cell transfer (CD4+CD25-), began to gain weight almost immediately after receiving the CD4+CD25+ T cells (Fig. 2a). This recovery was accompanied by curing of diarrhea and remission of epithelial hyperplasia, which had a pathology score of 3 (of maximum of 4) (Fig. 2b). By day 56, when the mice receiving CD4+CD25- T cells alone were euthanased because of excessive pathology, those mice treated on day 10 with CD4+CD25+ T cells had colonic appearance indistinguishable from normal mice. There was no significant difference among recipients of freshly isolated, TGF--cultured, or activated CD4+CD25+ T cells. For mice treated on day 21 with CD4+CD25+ T cells, TGF--cultured cells were more efficient than freshly isolated or activated CD4+CD25+ T cells in reversing the body weight of the disease mice. However, there was no difference in the pathology score among the mice treated with these three different preparations of CD4+CD25+ T cells (Fig. 2b). At the end of the experiment (day 56), mesenteric lymph node cells were cultured with plate-bound anti-CD3 Ab, and T cell proliferation and IFN- and IL-4 production were determined. T cells from mice transferred with CD4+CD25- T cells alone proliferated vigorously and produced significant amounts of IFN- and IL-4. In contrast, cells from mice transferred with the CD4+CD25- cells and treated with CD4+CD25+ T cells 10 or even 21 days later produced little or no proliferation or IFN- and IL-4 synthesis (Fig. 2c). These results therefore demonstrate clearly that CD4+CD25+ T cells are capable of curing an established wasting inflammatory disease. This was accompanied by a profound suppression of CD4+CD25- T cell reactivity in vivo. The mice were also monitored for Leishmania infection (Fig. 2d). Mice injected with CD4+CD25+ cells 10 days after CD4+CD25- cell plus infection developed lesion size indistinguishable from mice not receiving CD4+CD25+ cells up to 7 wk after infection, although by wk 5 the lesion in the CD4+CD25- alone group began to regress. There is thus no direct correlation between the parasite load and severity of colitis.
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We next investigated the mechanisms involved in the therapeutic action of CD4+CD25+ T cells. SCID mice transferred with CD4+CD25- T cells and infected with L. major were given CD4+CD25+ cells 21 days later. Some of the mice were also injected with Abs against IL-10R, TGF-, or CTLA4. Control mice were either untreated or injected with normal IgG. SCID mice given CD4+CD25- T cells alone developed colitis, as expected, and the disease outcome was not influenced by treatment with normal IgG or anti-CTLA4 Ab. CD4+CD25+ T cells markedly reversed the disease progression, as expected. However, the curative activity of the CD4+CD25+ cells was completely abolished by injecting the mice with anti-IL-10R, anti-CTLA4, or anti-TGF- Ab (Fig. 3). These results therefore demonstrate clearly that the therapeutic effect of CD4+CD25+ T cells in this model is critically dependent on IL-10, TGF-, and CTLA4. Finally, we investigated cytokine production by the mesenteric lymph node cells of the mice (harvested at the end of experiment on day 49) when activated with anti-CD3 Ab in vitro. Cells from mice transferred with CD4+CD25- T cells alone produced substantial amounts of IFN- and IL-4. These were profoundly suppressed by the transfer of CD4+CD25+ T cells on day 21. The suppression mediated by CD4+CD25+ T cells was not affected by the treatment of the mice with anti-IL-10R or anti-TGF- (Fig. 3c). In contrast, anti-CTLA4 Ab treatment reversed the suppressive effect of CD4+CD25+ T cells on IFN- and IL-4 synthesis. However, anti-CTLA4 Ab had little or no effect on the CD4+CD25- T cells alone (Fig. 3, b and c). It should also be noted that in the present model system, anti-glucocorticoid-induced TNFR family-related gene Ab (kindly provided by S. Sakaguchi, University of Kyoto, Kyoto, Japan) (13) had little or no influence on the therapeutic effect of CD4+CD25+ T cells in vivo (data not shown). We also monitored the Leishmania infection (Fig. 3d). As expected, mice injected with CD4+CD25- cells and infected with L. major developed lesion that progressed to wk 3, then began to regress. However, the lesion continued to progress when the mice were transferred with CD4+CD25+ cells on day 21 after infection. This lesion progression was not affected by the treatment of control IgG or anti-CTLA4 Ab, but reversed by anti-IL-10R Ab and partially halted by anti-TGF- Ab.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Data reported in this work demonstrate directly that CD4+CD25+ T cells can cure an established progressive inflammatory disease. Parallel with these results, it was recently reported that CD4+CD25+ T cells could also cure an IBD in rag1-/- mice induced by CD4+CD45RBlow T cells (18). We further advanced this observation by demonstrating that the therapy is critically associated with IL-10 and TGF- and CTLA4. Despite the general belief that CD4+CD25+ Treg cells suppress CD4+CD25- T cells by a cell contact-dependent mechanism in vitro, there is growing evidence that cytokine-dependent pathways are critical in the suppressive function of CD4+CD25+ T cells in vivo (19). The suppressive cytokines, IL-10 or TGF-, may be produced by CD4+CD25+ T cells or indirectly by CD4+CD25- T cells through infectious tolerance mechanism (20). It is important to note that although curing of the colitis by CD4+CD25+ T cells was accompanied by profound suppression of proliferation and cytokine production, the blocking of the therapeutic effect of CD4+CD25+ T cells by the anti-IL-10R and anti-TGF- Ab did not involve the reactivation of IFN-/IL-4 productions by CD4+CD25- T cells (Fig. 3). This result has two important implications: 1) CD4+CD25+ T cells could suppress CD4+CD25- T cells via an IL-10- and TGF--independent pathway in vivo, because the suppression persisted in the presence of neutralizing doses of anti-IL-10R and anti-TGF- Abs. 2) Colitis could persist in the absence of type 1 or 2 cytokines, because severe pathology continued in the absence of detectable levels of IFN- and IL-4. Interpretation 2 is consistent with previous reports showing that IFN- did not play a major role in the pathogenesis (21) or in sustaining (22) colitis. The mechanism for the pathogenesis of colitis is currently unknown, but it is clearly controllable by IL-10 and TGF-. This finding demonstrates the considerable functional overlap among CD4+CD25+ Treg cells, Treg 1 cells (IL-10 producing) (3), and Th3 cells (TGF--producing) (1) cells.
CD4+CD25+ T cells are the only CD4+ cells in the naive mouse that express the CTLA4 Ag (10, 15, 23, 24). It has been demonstrated that anti-CTLA4 Ab abrogated CD4+CD25+ T cell-mediated suppression in vitro and treatment of normal adult mice with anti-CTLA4-induced gastritis (23). Similarly, the protective effect of CD4+CD45RBlow T cells in colitis induced by CD4+CD45RBhigh T cells was abolished by treatment of the animals with anti-CTLA4 Ab in SCID mice (10). In contrast, the suppressive effect of CD4+CD25+ T cells on CD4+CD25- T cells in murine gastritis was apparently not affected by the presence of anti-CTLA4 Ab (24). In the colitis model reported in this work, the suppressive effect of CD4+CD25+ T cells was abolished by anti-CTLA4 Ab, consistent with the earlier observations for an important role of CTLA4 Ag in autoimmune diseases in vivo. However, the mechanism by which CTLA4 influences the suppressive effect of CD4+CD25+ T cells remains unclear. As CTLA4 is up-regulated following T cell activation, it is uncertain as to the target of the Ab. It is possible that anti-CTLA4 Ab blocked CTLA4 on the Treg cells. Alternatively, the Ab could activate CD4+CD25- T cells. This seems unlikely because anti-CTLA4 Ab treatment of mice transferred with CD4+CD25- T cells alone did not affect the pathogenicity of these cells. Instead, the Ab modestly down-regulated IL-4 production by the transferred CD4+CD25- T cells. However, the possibility that anti-CTLA4 Ab may render the CD4+CD25- T cells refractory to the suppressive effect of the Treg cells by masking their CTLA4 Ag cannot be excluded.
We also monitored the progression of Leishmania infection throughout the experiments. The effect of CD4+CD25+ cell transfer on the infection depends on the timing of the transfer relative to CD4+CD25- cell reconstitution of the SCID mice. SCID mice reconstituted with CD4+CD25+ T cells alone developed minimal lesion for the first 3 wk after infection. Thereafter, the lesion progressed inexorably. In contrast, SCID mice transferred with CD4+CD25- T cells developed significant lesion for the first 3 wk and then regressed and maintained at a low level. The lesion size directly correlated with parasite loads. This pattern of infection is consistent with previous reports (11, 12). The reason for this biphasic response is currently unclear and is beyond the scope of this report. When CD4+CD25+ cells were transferred 10 days after CD4+CD25- cells (freshly isolated, or activated with anti-CD3 Ab in vitro, or cultured with TGF-), the infection that developed was indistinguishable from that of mice injected with CD4+CD25- cells alone for the first 5 wk; thereafter, the infection in the CD4+CD25+ cell recipients continued to progress, while that of the mice receiving CD4+CD25- cells alone began to regress. In contrast, when CD4+CD25+ cells were transferred 21 days after CD4+CD25- cells, the infection continued to progress, while that of mice injected with CD4+CD25- cells alone began to regress. The relation between the degree of Leishmania infection and severity of colitis appears to be complex. For example, whereas both anti-IL-10R and anti-CTLA4 Ab treatment abrogated the colitis-protective effect of CD4+CD25+ cells, only anti-IL-10R Ab treatment significantly reduced the infection-promoting effect of CD4+CD25+ cells. This lesion-reduction effect of anti-IL-10R Ab is consistent with a recent report (25). Furthermore, although anti-TGF- Ab significantly reduced the severity of colitis, the Ab also reduced the Leishmania infection, albeit delayed (Fig. 3d). The effect of anti-TGF- Ab on Leishmania infection is again consistent with a previous report (26). Thus, it is unlikely that the curative effect of CD4+CD25+ cells is due to an indirect effect on Leishmania infection.
In summary, data reported in this work directly demonstrate the therapeutic role of CD4+CD25+ T cells in severe inflammatory colitis. Furthermore, we show that the therapeutic effect is critically dependent on IL-10, TGF-, and CTLA4. The results also suggest that expansion of autologous CD4+CD25+ T cells in vitro, followed by reinfusion of these cells, may hold considerable therapeutic potential in treating severe clinical chronic inflammatory diseases.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. F. Y. Liew or Dr. Damo Xu, Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, G11 6NT, U.K. E-mail addresses: F.Y.Liew{at}clinmed.gla.ac.uk or d.xu{at}clinmed.gla.ac.uk
3 Abbreviations used in this paper: Treg, regulatory T cell; IBD, inflammatory bowel disease.
Received for publication May 2, 2003. Accepted for publication September 3, 2003.
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References |
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-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155:1151.[Abstract]
in the pathogenesis of experimental colitis in mice. J. Gastroenterol. Hepatol. 18:578.[Medline]
, plays a major role in sustaining the chronic phase of colitis in IL-10-deficient mice. J. Immunol. 161:3143. treatment promotes rapid healing of Leishmania major infection in mice by enhancing in vivo nitric oxide production. J. Immunol. 162:974.This article has been cited by other articles:
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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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 O. Saitoh and Y. Nagayama Regulation of Graves' Hyperthyroidism with Naturally Occurring CD4+CD25+ Regulatory T Cells in a Mouse Model Endocrinology, May 1, 2006; 147(5): 2417 - 2422. [Abstract] [Full Text] [PDF]
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T. Kanai, K. Tanimoto, Y. Nemoto, R. Fujii, S. Makita, T. Totsuka, and M. Watanabe Naturally arising CD4+CD25+ regulatory T cells suppress the expansion of colitogenic CD4+CD44highCD62L- effector memory T cells Am J Physiol Gastrointest Liver Physiol, May 1, 2006; 290(5): G1051 - G1058. [Abstract] [Full Text] [PDF]
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C. Baecher-Allan, E. Wolf, and D. A. Hafler MHC class II expression identifies functionally distinct human regulatory T cells. J. Immunol., April 15, 2006; 176(8): 4622 - 4631. [Abstract] [Full Text] [PDF]
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M. Kramer, M. G. Netea, D. J. de Jong, B. J. Kullberg, and G. J. Adema Impaired dendritic cell function in Crohn's disease patients with NOD2 3020insC mutation J. Leukoc. Biol., April 1, 2006; 79(4): 860 - 866. [Abstract] [Full Text] [PDF]
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M. L. Drakes, T. G. Blanchard, and S. J. Czinn Colon lamina propria dendritic cells induce a proinflammatory cytokine response in lamina propria T cells in the SCID mouse model of colitis J. Leukoc. Biol., December 1, 2005; 78(6): 1291 - 1300. [Abstract] [Full Text] [PDF]
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 F Y Liew, M Patel, and D Xu Toll-like receptor 2 signalling and inflammation Ann Rheum Dis, November 1, 2005; 64(suppl_4): iv104 - iv105. [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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M. J. McGeachy, L. A. Stephens, and S. M. Anderton Natural Recovery and Protection from Autoimmune Encephalomyelitis: Contribution of CD4+CD25+ Regulatory Cells within the Central Nervous System J. Immunol., September 1, 2005; 175(5): 3025 - 3032. [Abstract] [Full Text] [PDF]
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 V. Gillan and E. Devaney Regulatory T Cells Modulate Th2 Responses Induced by Brugia pahangi Third-Stage Larvae Infect. Immun., July 1, 2005; 73(7): 4034 - 4042. [Abstract] [Full Text] [PDF]
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M. Patel, D. Xu, P. Kewin, B. Choo-Kang, C. McSharry, N. C. Thomson, and F. Y. Liew TLR2 Agonist Ameliorates Established Allergic Airway Inflammation by Promoting Th1 Response and Not via Regulatory T Cells J. Immunol., June 15, 2005; 174(12): 7558 - 7563. [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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J. G. Heuer, T. Zhang, J. Zhao, C. Ding, M. Cramer, K. L. Justen, S. L. Vonderfecht, and S. Na Adoptive Transfer of In Vitro-Stimulated CD4+CD25+ Regulatory T Cells Increases Bacterial Clearance and Improves Survival in Polymicrobial Sepsis J. Immunol., June 1, 2005; 174(11): 7141 - 7146. [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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J. T. Lin, S. L. Martin, L. Xia, and J. D. Gorham TGF-{beta}1 Uses Distinct Mechanisms to Inhibit IFN-{gamma} Expression in CD4+ T Cells at Priming and at Recall: Differential Involvement of Stat4 and T-bet J. Immunol., May 15, 2005; 174(10): 5950 - 5958. [Abstract] [Full Text] [PDF]
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J. Minguillon, B. Morancho, S.-J. Kim, M. Lopez-Botet, and J. Aramburu Concentrations of cyclosporin A and FK506 that inhibit IL-2 induction in human T cells do not affect TGF-{beta}1 biosynthesis, whereas higher doses of cyclosporin A trigger apoptosis and release of preformed TGF-{beta}1 J. Leukoc. Biol., May 1, 2005; 77(5): 748 - 758. [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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S. M. Pop, C. P. Wong, D. A. Culton, S. H. Clarke, and R. Tisch Single cell analysis shows decreasing FoxP3 and TGF{beta}1 coexpressing CD4+CD25+ regulatory T cells during autoimmune diabetes J. Exp. Med., April 18, 2005; 201(8): 1333 - 1346. [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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B. Valzasina, C. Guiducci, H. Dislich, N. Killeen, A. D. Weinberg, and M. P. Colombo Triggering of OX40 (CD134) on CD4+CD25+ T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR Blood, April 1, 2005; 105(7): 2845 - 2851. [Abstract] [Full Text] [PDF]
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S. Huber, C. Schramm, H. A. Lehr, A. Mann, S. Schmitt, C. Becker, M. Protschka, P. R. Galle, M. F. Neurath, and M. Blessing Cutting Edge: TGF-{beta} Signaling Is Required for the In Vivo Expansion and Immunosuppressive Capacity of Regulatory CD4+CD25+ T Cells J. Immunol., December 1, 2004; 173(11): 6526 - 6531. [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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C. Vasu, B. S. Prabhakar, and M. J. Holterman Targeted CTLA-4 Engagement Induces CD4+CD25+CTLA-4high T Regulatory Cells with Target (Allo)antigen Specificity J. Immunol., August 15, 2004; 173(4): 2866 - 2876. [Abstract] [Full Text] [PDF]
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A. E. Herman, G. J. Freeman, D. Mathis, and C. Benoist CD4+CD25+ T Regulatory Cells Dependent on ICOS Promote Regulation of Effector Cells in the Prediabetic Lesion J. Exp. Med., June 7, 2004; 199(11): 1479 - 1489. [Abstract] [Full Text] [PDF]
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20% of their initial body weight, the mice were sacrificed and histopathology of the colon was determined (as described in Ref. 
