HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tang, Q. Articles by Bluestone, J. A. Search for Related Content PubMed PubMed Citation Articles by Tang, Q. Articles by Bluestone, J. A.

Cutting Edge: CD28 Controls Peripheral Homeostasis of CD4⁺CD25⁺ Regulatory T Cells ¹

Qizhi Tang^*, Kammi J. Henriksen^*, Elisa K. Boden^*, Aaron J. Tooley^*, Jianqin Ye^*, Sumit K. Subudhi, Xin X. Zheng, Terry B. Strom and Jeffrey A. Bluestone^2,*

^* University of California San Francisco Diabetes Center, University of California, San Francisco, CA 94143; Committee on Immunology, University of Chicago, Chicago, IL 60637; and Division of Immunology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215

	Abstract

Top Abstract Introduction Materials and Methods Results and Discussion References

 
CD28/B7 blockade leads to exacerbated autoimmune disease in the nonobese diabetic mouse strain as a result of a marked reduction in the number of CD4⁺CD25⁺ regulatory T cells (Tregs). Herein, we demonstrate that CD28 controls both thymic development and peripheral homeostasis of Tregs. CD28 maintains a stable pool of peripheral Tregs by both supporting their survival and promoting their self-renewal. CD28 engagement promotes survival by regulating IL-2 production by conventional T cells and CD25 expression on Tregs.

	Introduction

Top Abstract Introduction Materials and Methods Results and Discussion References

 
In both mice and humans, CD4⁺CD25⁺ regulatory T cells (Tregs)³ constitute 5–15% of peripheral CD4⁺ T cells and are immunosuppressive in vivo and in vitro (1, 2). Thymic-derived Tregs have been shown to regulate autoimmune disease via active suppression of self-reactive T cells in various models of autoimmunity (3). Mice engineered to express both a transgenic TCR and its cognate Ag in the thymus have an increased percentage of Tregs in the thymus and the periphery (4, 5), suggesting that Tregs develop from self-reactive T cells that have escaped negative selection. Moreover, there is evidence to indicate that autoantigens and IL-2-dependent events are essential for the maintenance and/or induction of Ag-specific Tregs in the periphery (6, 7).

Previously, we showed that Tregs control development of diabetes in the nonobese diabetic (NOD) mouse model of spontaneous autoimmune diabetes. In addition, in the absence of CD28-mediated costimulatory signals, NOD mice developed exacerbated diabetes associated with a profound decrease in the number of peripheral Tregs (8). Prevention of disease could be achieved by the reconstitution of Tregs from wild-type (WT) NOD mice, implicating CD28/B7 interactions in promoting regulatory function and peripheral homeostasis of Tregs. The role of CD28 costimulation in classical T cell activation has been investigated extensively. Because Tregs are naturally anergic and do not produce IL-2 (a major CD28-dependent event), it is unclear how CD28 regulates Treg development and homeostasis.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Mice

Six- to 10-wk-old C57BL/6 and BALB/c mice (Charles River Breeding Laboratories, Wilmington, MA), NOD mice (Taconic Farms, Germantown, NY), CD28-deficient mice on BALB/c background, and Bcl-x_L transgenic mice on a C57BL/6 background were housed under specific pathogen-free conditions at the Animal Barrier Facility (University of California, San Francisco, CA).

Abs and other reagents

mAbs: 145-2C11 (anti-CD3), AT83a (rat anti-Thy1.2), 16-10A1 (anti-B7-1), and GL-1 (anti-B7-2) were prepared in our laboratory. Murine CTLA4 Ig was a generous gift from Genetics Institute (Cambridge, MA). Recombinant human (rh) IL-2 was a gift from Chiron (Emeryville, CA). Fluorochrome-labeled mAbs against CD25 (7D4), CD62L (Mel-14), and CD4 (GK1.5) were purchased from Southern Biotechnology Associates (Birmingham, AL). Allophycocyanin and PerCP-labeled mAbs against CD4 (RM4-5) were purchased from BD PharMingen (San Diego, CA). Biotin-labeled anti-glucocorticoid-induced TNFR family related (GITR) Abs were purchased from R&D Systems (Minneapolis, MN). CFSE was purchased from Molecular Probes (Eugene, OR).

Cell sorting and flow cytometry

Tregs were sorted from lymph node (LN) and spleen cells on the Mo-Flo cytometer (Cytomation, Fort Collins, CO) based on the expression of CD4, CD25, and CD62 ligand (CD62L) to >95% purity. For some experiments, CD4⁺ T cells were enriched from pooled LN and spleens by negative selection on autoMACS (Miltenyi Biotec, Auburn, CA), and cultured overnight at 5 x 10⁶ cell/ml in 20 U/ml rhIL-2 in complete medium as previously described (8). Tregs were sorted the next day as described above. Flow cytometric analyses were performed on a FACSCalibur flow cytometer with CellQuest software (BD Biosciences, San Jose, CA).

Adoptive transfer and Ab/cytokine administration

Sorted T cells were labeled with 1.5 µM CFSE, and 1–3 x 10⁶ cells were transferred via retro-orbital injection. The recipient mice were treated by i.p. injection with a mixture of anti-B7-1 and anti-B7-2 Abs (100 µg each) in PBS, 200 µg of control mAb (rat anti-human Bw6), CTLA4 Ig, or PBS as specified in figure legends. In some experiments, a rat anti-human HLA-Bw6 mAb was administered as control for the anti-B7 mAbs, whereas PBS was used in other experiments. No observable differences were noted among control mAb-, PBS-treated, or untreated mice.

Real-time PCR analysis of steady state IL-2 mRNA in spleens

Total RNA was extracted using TRIzol reagent (Invitrogen, Carlsbad, CA) from spleens of WT and CD28^-/- BALB/c mice immediately after sacrifice. cDNA was synthesized from 2 µg of each RNA sample using SuperScript II RNase H- reverse transcriptase and oligo dT as primer (Invitrogen), and 25 ng of the cDNA was used in each real-time PCR for IL-2 or hypoxanthine phosphoribosyltransferase (HPRT). Primers and probes for both genes were purchased as reagent kits from Applied Biosystems (Foster City, CA). The real-time PCR was performed on ABI Prizm 7700 using TaqMan Universal PCR master mix (Applied Biosystems) in duplicates and the average threshold cycles (Ct) of the duplicate were used to calculate the fold change between WT and CD28KO mice. Ct for HPRT were used to normalize the samples, and fold change was calculated using the following formula: fold change = 2^-n, n = ((CD28^-/- Ct_IL-2 - CD28^-/- Ct_HPRT) - (WT Ct_IL-2 - WT Ct_HPRT)).

	Results and Discussion

Top Abstract Introduction Materials and Methods Results and Discussion References

 
CD28 controls thymic development of CD4⁺CD25⁺ regulatory T cells

A comparison of the thymic CD4 single-positive (SP) CD25⁺ T cells in WT and CD28-deficient mice demonstrated that disruption of the CD28/B7 pathway resulted in a dramatic (80%) reduction in both the percentage and the number of CD4 SP CD25⁺ T cells in the thymus (Fig. 1A). Similarly, mice treated with a combination of anti-B7-1 and anti-B7-2 Abs every other day for 10 days resulted in a 66% reduction in the number of CD4⁺SP CD25⁺ T cells in the thymus compared with PBS-treated littermate controls (Fig. 1B). Thus, our data suggest that Tregs develop in a CD28/B7-dependent manner in adult mice.

View larger version (21K): [in this window] [in a new window]   FIGURE 1. CD28 is essential for both thymic development of Tregs and their peripheral homeostasis. A, Percentages of CD25+ cells among CD4 SP thymocytes in WT (n = 3) or CD28-/- BALB/c mice (n = 3) were determined by flow cytometry. B, WT NOD mice were injected with anti-B7-1 and anti-B7-2 (100 µg each, n = 3) or PBS (n = 2) every other day for 10 days. On day 10, the percentages of CD25+ cells among CD4+ SP thymocytes were determined. C, BALB/c mice were thymectomized (n = 8), sham-thymectomized (n = 4), or not treated (n = 5) on day 0 and injected with PBS or anti-B7-1 and anti-B7-2 (100 µg each) on days 5, 7, 9, 11, and 13. The percentages of Tregs in CD4 gate of lymph node cells were determined on day 14. Each circle represents one animal and the black bar represents the mean of the group. Results are representative of two independent experiments.

The treatment of NOD mice with CTLA4 Ig fusion protein results in a rapid reduction in the number of Tregs in the LN and spleen (8). Similar results have been obtained using anti-B7 Abs in all mouse strains tested (BALB/c, B6, and NOD, data not shown). However, it was possible that the depletion of Tregs in the periphery following CD28/B7 blockade was a consequence of the decreased generation of these cells in the thymus as opposed to a direct effect on the peripheral Treg population. The Treg population in adult thymectomized mice was significantly reduced following anti-B7 treatment (Fig. 1C), comparable to that observed in sham-thymectomized animals. Moreover, unlike CD28^-/- mice, young (10–14 days) CTLA-4^-/- mice have normal levels of CD62L^high Tregs in the periphery (data not shown). These results suggest that CD28 is important both for the development of Tregs in the thymus and for their maintenance in the periphery.

Treg proliferation and survival depends on CD28 costimulation

Purified labeled CD4⁺CD62L^highCD25⁺ (Tregs) or CD4⁺CD62L^highCD25^- cells were transferred into secondary hosts and the recipients were treated with a combination of anti-B7-1 and anti-B7-2 mAbs or control Abs with irrelevant specificity. The numbers of labeled Tregs in the LN and spleens of recipient mice were determined by flow cytometry based on the coexpression of CD4 and CFSE on days 15 and 30 after cell transfer. The total number of cells recovered at various time points after transfer was estimated to be 10% of the initial input. This relatively low rate of recovery is most likely due to nonspecific trapping of transferred cell in tissues immediately after injection. It has been documented that despite the low recovery, the remaining transferred cells exhibited homing and activation patterns predicted for their endogenous counterparts (9). Therefore, we believe that the cells recovered from the LN and spleens in our experiments are representative of the transferred cells and are likely to reflect the behavior of the corresponding endogenous cell population. In contrast to the purported "anergic" phenotype of Tregs observed in vitro (10, 11), the Tregs underwent brisk proliferation in vivo, with 10–15% diluting the CFSE label within 2 wk after transfer (data not shown) and up to 40% 30 days after transfer (18% in the experiment shown in Fig. 2A). Moreover, because we could not detect transferred cells once their CFSE label is at background level, the actual proportion of transferred Tregs that have undergone proliferation is likely to be higher than our estimation. In contrast, only 6.5% of the CD25^- cells transferred in the same manner showed CFSE dilution by day 30 (Fig. 2A). The recipient mice were not lymphopenic, therefore the proliferation observed represented the true steady state homeostatic activity of these cells. Moreover, the proliferation was CD28-dependent, as it was almost completely blocked by anti-B7 mAb treatment (Fig. 2, B and C). Because this block in proliferation was observed at all time points examined (days 1, 7, 15, and 30), we think it is very unlikely that a subpopulation of cells have lost all CFSE and escaped detection. In addition, this is not due to killing of the Tregs by direct binding of the anti-B7 mAb because a similar reduction in Treg proliferation was observed when WT Tregs were transferred to mice that were deficient in both B7-1 and B7-2 (data not shown), demonstrating that B7 expression on the host cells was essential for Treg proliferation. These results support the notion that Tregs express TCRs that react with self Ags (4, 5, 6), and continuously respond to autoantigens in a costimulation-dependent manner to maintain their homeostasis in vivo.

View larger version (26K): [in this window] [in a new window]   FIGURE 2. CD28 regulates both proliferation and survival of Tregs in the periphery. Sorted CFSE-labeled Tregs or CD4+CD62L+CD25- cells were transferred to syngeneic mice, proliferation and cell survival were analyzed on days 15 and 30 after transfer. Representative dot plots of LN cells harvested on day 30 in control-treated animals (A) and anti-B7-treated animals (B) are shown. Proliferation of CD25+ cells on day 15 (C, n = 3 in each group) and the number of nondividing CFSEhigh cells on indicated days after transfer (D, n = 3 in each group) were determined by flow cytometry. Symbols are as described for Fig. 1. Results are representative of five independent experiments.

Treg survival depends on both IL-2 and B7

IL-2 has been shown to be essential for Treg homeostasis, and mice deficient in IL-2 or IL-2R have very low numbers of Tregs in the periphery (7, 12, 13, 14) and develop rampant systemic autoimmune diseases (15, 16, 17). Moreover, CD28 plays a critical role in IL-2 production by activated T cells (18), and the steady state IL-2 mRNA was 2- to 5-fold less in normal unperturbed CD28^-/- mice compared with that in normal WT mice (Fig 3A). To determine whether the diminished steady state IL-2 production in CD28^-/- mice affected normal Treg homeostasis, the survival of purified WT Tregs transferred into WT and CD28^-/- hosts was compared. One month after transfer into CD28^-/- recipients, WT Tregs were barely detectable in the LNs and spleens (Fig. 3, B and C). These results demonstrated that CD28 expression on Tregs was insufficient to support Treg homeostasis. Thus, CD28 functioned on conventional T cells to regulate Treg survival through the induction of Treg-extrinsic survival factor(s), such as IL-2. To determine whether exogenous IL-2 could overcome the Treg survival defect in CD28^-/- mice, we precultured Tregs in 20 U/ml IL-2 overnight and examined their survival in WT or CD28^-/- hosts. The short-term culture in IL-2 did not significantly up-regulate CD25 expression on the Tregs (data not shown). In contrast, the IL-2 treatment restored Treg homeostasis in IL-2^-/- mice (data not shown) and completely protected the Tregs in the CD28^-/- hosts for the observation period (Fig. 3, D and E). Thus, the IL-2 level is likely to be one of the limiting factors in sustaining Treg homeostasis in CD28^-/- mice.

View larger version (33K): [in this window] [in a new window]   FIGURE 3. Both IL-2 and B7 are necessary for Treg survival. A, Steady state IL-2 mRNA level was determined in the spleens of WT (n = 4) and CD28-/- (n = 5) mice by reverse transcription of RNA followed by real-time PCR analysis. B and C, Tregs cells were purified from WT BALB/c mice and transferred to either WT or CD28-/- BALB/c mice after CFSE labeling. Representative dot plots (B) and total number of CFSE+ cells (C, n = 3 in WT and 2 in CD28-/-) in the LN harvested on day 30 after transfer are shown. D and E, WT BALB/c Tregs were purified from LN and spleens after overnight culture in 20 U/ml IL-2 and transferred to WT (n = 2) or CD28-/- (n = 4) BALB/c hosts after CSFE labeling. Representative dot plots (D) and total number of CFSE+ cells (E) in the LN harvested on day 30 after transfer are shown. F, WT BALB/c Tregs were purified from LN and spleens after overnight culture in 20 U/ml IL-2 and transferred to WT BALB/c host after CFSE labeling. The mice were then treated with anti-B7 mAbs (n = 2) or PBS (n = 2) every third day for 30 days. Numbers of CFSEhigh cells in LN were determined by flow cytometry on day 30 after cell transfer. Symbols are as described for Fig. 1. Results are representative of two (A–C), three (D and E), and five (F) independent experiments.

CD28 maintains a high level of CD25 expression on Tregs

Costimulation through CD28 has been shown to be necessary for inducing several cell intrinsic survival factors, such as Bcl-x_L (19)_. Therefore, we tested whether these molecules were involved in CD28 regulation of Treg survival. Transgenic mice expressing Bcl-x_L under the control of the Lck proximal promoter were treated with CTLA4 Ig. Although CD4⁺CD25⁺ in these transgenic mice overexpress Bcl-x_L, Tregs were not protected from depletion after CD28/B7 blockade (Fig. 4A). CD28-dependent OX40 induction on CD4⁺ T cells has been implicated in promoting T cell survival and the generation of memory T cells (20, 21). In addition, OX40 was expressed on resting WT, but not on CD28^-/- Tregs (data not shown). However, unlike CD28^-/- mice, OX40^-/- mice have normal level of Tregs in the periphery (Fig. 4B) and thymus (data not shown). Taken together, these results suggest that CD28 regulation of Treg survival was independent of Bcl-x_L and OX40.

View larger version (28K): [in this window] [in a new window]   FIGURE 4. CD28 regulation of Treg survival is independent of Bcl-xL and OX40. A, Bcl-xL transgenic and WT littermates were treated with CTLA4 Ig or PBS as control every other day for 10 days. Percentages of CD25+ cells in the CD4 gate in the LN were determined by flow cytometry. B, Percentages of Tregs in the CD4 gate in OX40-/- mice were compared with those in WT and CD28-/- mice (n = 4 in each group). C and D, Tregs were purified from WT BALB/c mice and transferred to syngeneic hosts after CFSE labeling. The recipient mice were treated with either anti-B7 mAbs or control mAb every third day for 15 days (n = 3 in each group). Levels of CD25 and GITR expression on CD4+ CFSEhigh cells were determined by flow cytometry on day 15 after cell transfer. Representative dot plots (D) and charts of MFI of CD25 staining on CD4+ CFSE+ cells are shown. The position of the quadrants was set such that all the endogenous Tregs fall in the upper right quadrant and all the CD4+CD25- cells fall in the left two quadrants. The numbers in dot plots indicate the percentages of transferred cells in respective quadrants. Symbols are as described for Fig. 1. Results are representative of two (A and B) and five (C and D) independent experiments.

In conclusion, we have demonstrated that CD28 provides a unique costimulatory signal to promote thymic development and peripheral homeostasis of Tregs. In addition, CD28 maintains a stable pool of peripheral Tregs by supporting both their self-renewal and their survival. These functions of CD28 were independent of Bcl-x_L or OX40 and were mediated through IL-2 and CD25. We propose that CD28 directly regulates Treg proliferation possibly by increasing TCR signaling strength, and indirectly regulates Treg survival by promoting IL-2 production by conventional T cells and by up-regulation of CD25 on Tregs.

Understanding the mechanisms of CD28/B7 costimulation in the maintenance of Tregs has important implications for the treatment of autoimmunity and transplant rejection via CD28 blockade. Although treatments such as CTLA4 Ig block T cell activation, they also deplete tolerance-promoting Tregs. Therefore, it will be important to determine the signals provided by CD28/B7 interactions that maintain the development and survival of regulatory T cells. Ultimately, we may be able to harness these signals to generate Tregs that promote tolerance in the setting of autoimmunity and transplantation.

	Acknowledgments

 
We thank Shuwei Jiang and Cliff McArthur for technical help on cell sorting and Paul Wegfahrt for mouse handling. We also thank Dr. Nigel Killeen for providing the OX40-deficient mice. We thank Drs. Abul Abbas, Lucy Walker, and Jens Lohr for helpful discussion on the project and critical reading of the manuscript.

	Footnotes

 
¹ This work is supported by National Institutes and Health Grants AI466430 (to J.A.B.) and F32 AI10360 (to Q.T.). E.K.B. is a Howard Hughes Medical Institute Medical Student Fellow.

² Address correspondence and reprint requests to Dr. Jeffrey A. Bluestone, University of California San Francisco Diabetes Center, University of California, San Francisco, Box 0540, 513 Parnassus Avenue, San Francisco, CA 94143-0540. E-mail address: jbluest{at}diabetes.ucsf.edu

³ Abbreviations used in this paper: Treg, regulatory T cells; NOD, nonobese diabetic; WT, wild type; GITR, glucocorticoid-induced TNFR family related; LN, lymph node; CD62L, CD62 ligand; rh, recombinant human; HPRT, hypoxanthine phosphoribosyltransferase; Ct, threshold cycle; SP, single positive.

Received for publication June 27, 2003. Accepted for publication August 12, 2003.

	References

Top Abstract Introduction Materials and Methods Results and Discussion References

 

1. Sakaguchi, S., N. Sakaguchi, J. Shimizu, S. Yamazaki, T. Sakihama, M. Itoh, Y. Kuniyasu, T. Nomura, M. Toda, T. Takahashi. 2001. Immunologic tolerance maintained by CD25⁺CD4⁺ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol. Rev. 182:18.[Medline]
2. Shevach, E. M.. 2002. CD4⁺CD25⁺ suppressor T cells: more questions than answers. Nat. Rev. Immunol. 2:389.[Medline]
3. Chatenoud, L., B. Salomon, J. A. Bluestone. 2001. Suppressor T cells–they’re back and critical for regulation of autoimmunity!. Immunol. Rev. 182:149.[Medline]
4. Jordan, M. S., A. Boesteanu, A. J. Reed, A. L. Petrone, A. E. Holenbeck, M. A. Lerman, A. Naji, A. J. Caton. 2001. Thymic selection of CD4⁺CD25⁺ regulatory T cells induced by an agonist self-peptide. Nat. Immunol. 2:301.[Medline]
5. Apostolou, I., A. Sarukhan, L. Klein, H. von Boehmer. 2002. Origin of regulatory T cells with known specificity for antigen. Nat. Immunol. 3:756.[Medline]
6. Seddon, B., D. Mason. 1999. Peripheral autoantigen induces regulatory T cells that prevent autoimmunity. J. Exp. Med. 189:877.[Abstract/Free Full Text]
7. Wolf, M., A. Schimpl, T. Hunig. 2001. Control of T cell hyperactivation in IL-2-deficient mice by CD4⁺CD25^- and CD4⁺CD25⁺ T cells: evidence for two distinct regulatory mechanisms. Eur. J. Immunol. 31:1637.[Medline]
8. Salomon, B., D. J. Lenschow, L. Rhee, N. Ashourian, B. Singh, A. Sharpe, J. A. Bluestone. 2000. B7/CD28 costimulation is essential for the homeostasis of the CD4⁺CD25⁺ immunoregulatory T cells that control autoimmune diabetes. Immunity 12:431.[Medline]
9. Reinhardt, R. L., A. Khoruts, R. Merica, T. Zell, M. K. Jenkins. 2001. Visualizing the generation of memory CD4 T cells in the whole body. Nature 410:101.[Medline]
10. Thornton, A. M., E. M. Shevach. 1998. CD4⁺CD25⁺ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 188:287.[Abstract/Free Full Text]
11. Itoh, M., T. Takahashi, N. Sakaguchi, Y. Kuniyasu, J. Shimizu, F. Otsuka, S. Sakaguchi. 1999. Thymus and autoimmunity: production of CD25⁺CD4⁺ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J. Immunol. 162:5317.[Abstract/Free Full Text]
12. Furtado, G. C., M. A. Curotto de Lafaille, N. Kutchukhidze, J. J. Lafaille. 2002. Interleukin 2 signaling is required for CD4⁺ regulatory T cell function. J. Exp. Med. 196:851.[Abstract/Free Full Text]
13. Almeida, A. R., N. Legrand, M. Papiernik, A. A. Freitas. 2002. Homeostasis of peripheral CD4⁺ T cells: IL-2R and IL-2 shape a population of regulatory cells that controls CD4⁺ T cell numbers. J. Immunol. 169:4850.[Abstract/Free Full Text]
14. Malek, T. R., A. Yu, V. Vincek, P. Scibelli, L. Kong. 2002. CD4 regulatory T cells prevent lethal autoimmunity in IL-2R-deficient mice: implications for the nonredundant function of IL-2. Immunity 17:167.[Medline]
15. Sadlack, B., H. Merz, H. Schorle, A. Schimpl, A. C. Feller, I. Horak. 1993. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75:253.[Medline]
16. Willerford, D. M., J. Chen, J. A. Ferry, L. Davidson, A. Ma, F. W. Alt. 1995. Interleukin-2 receptor chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3:521.[Medline]
17. Schorle, H., T. Holtschke, T. Hunig, A. Schimpl, I. Horak. 1991. Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature 352:621.[Medline]
18. June, C. H., J. A. Bluestone, L. M. Nadler, C. B. Thompson. 1994. The B7 and CD28 receptor families. Immunol. Today 15:321.[Medline]
19. Alegre, M. L., K. A. Frauwirth, C. B. Thompson. 2001. T-cell regulation by CD28 and CTLA-4. Nat. Rev. Immunol. 1:220.[Medline]
20. Rogers, P. R., J. Song, I. Gramaglia, N. Killeen, M. Croft. 2001. OX40 promotes Bcl-x_L and Bcl-2 expression and is essential for long-term survival of CD4 T cells. Immunity 15:445.[Medline]
21. Gramaglia, I., A. Jember, S. D. Pippig, A. D. Weinberg, N. Killeen, M. Croft. 2000. The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion. J. Immunol. 165:3043.[Abstract/Free Full Text]
22. McHugh, R. S., M. J. Whitters, C. A. Piccirillo, D. A. Young, E. M. Shevach, M. Collins, M. C. Byrne. 2002. CD4⁺CD25⁺ immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16:311.[Medline]
23. Shimizu, J., S. Yamazaki, T. Takahashi, Y. Ishida, S. Sakaguchi. 2002. Stimulation of CD25⁺CD4⁺ regulatory T cells through GITR breaks immunological self-tolerance. Nat. Immunol. 3:135.[Medline]

This article has been cited by other articles:

				L. K. Swee, N. Bosco, B. Malissen, R. Ceredig, and A. Rolink Expansion of peripheral naturally occurring T regulatory cells by Fms-like tyrosine kinase 3 ligand treatment Blood, June 18, 2009; 113(25): 6277 - 6287. [Abstract] [Full Text] [PDF]

				L. L. Molinero, J. Yang, T. Gajewski, C. Abraham, M. A. Farrar, and M.-L. Alegre CARMA1 Controls an Early Checkpoint in the Thymic Development of FoxP3+ Regulatory T Cells J. Immunol., June 1, 2009; 182(11): 6736 - 6743. [Abstract] [Full Text] [PDF]

				J. Kurtz, F. Raval, C. Vallot, J. Der, and M. Sykes CTLA-4 on alloreactive CD4 T cells interacts with recipient CD80/86 to promote tolerance Blood, April 9, 2009; 113(15): 3475 - 3484. [Abstract] [Full Text] [PDF]

				P. Zhou, X. Zheng, H. Zhang, Y. Liu, and P. Zheng B7 Blockade Alters the Balance between Regulatory T Cells and Tumor-reactive T Cells for Immunotherapy of Cancer Clin. Cancer Res., February 1, 2009; 15(3): 960 - 970. [Abstract] [Full Text] [PDF]

				A. I. Proietto, S. van Dommelen, P. Zhou, A. Rizzitelli, A. D'Amico, R. J. Steptoe, S. H. Naik, M. H. Lahoud, Y. Liu, P. Zheng, et al. Dendritic cells in the thymus contribute to T-regulatory cell induction PNAS, December 16, 2008; 105(50): 19869 - 19874. [Abstract] [Full Text] [PDF]

				N. Beyersdorf, X. Ding, G. Blank, K. M. Dennehy, T. Kerkau, and T. Hunig Protection from graft-versus-host disease with a novel B7 binding site-specific mouse anti-mouse CD28 monoclonal antibody Blood, November 15, 2008; 112(10): 4328 - 4336. [Abstract] [Full Text] [PDF]

				E. Sgouroudis, A. Albanese, and C. A. Piccirillo Impact of Protective IL-2 Allelic Variants on CD4+Foxp3+ Regulatory T Cell Function In Situ and Resistance to Autoimmune Diabetes in NOD Mice J. Immunol., November 1, 2008; 181(9): 6283 - 6292. [Abstract] [Full Text] [PDF]

				A. Dolganiuc and G. Szabo T cells with regulatory activity in hepatitis C virus infection: what we know and what we don't J. Leukoc. Biol., September 1, 2008; 84(3): 614 - 622. [Abstract] [Full Text] [PDF]

				F. Guo, C. Iclozan, W.-K. Suh, C. Anasetti, and X.-Z. Yu CD28 Controls Differentiation of Regulatory T Cells from Naive CD4 T Cells J. Immunol., August 15, 2008; 181(4): 2285 - 2291. [Abstract] [Full Text] [PDF]

				T. N. Golovina, T. Mikheeva, M. M. Suhoski, N. A. Aqui, V. C. Tai, X. Shan, R. Liu, R. R. Balcarcel, N. Fisher, B. L. Levine, et al. CD28 Costimulation Is Essential for Human T Regulatory Expansion and Function J. Immunol., August 15, 2008; 181(4): 2855 - 2868. [Abstract] [Full Text] [PDF]

				A. L. Tang, J. R. Teijaro, M. N. Njau, S. S. Chandran, A. Azimzadeh, S. G. Nadler, D. M. Rothstein, and D. L. Farber CTLA4 Expression Is an Indicator and Regulator of Steady-State CD4+FoxP3+ T Cell Homeostasis J. Immunol., August 1, 2008; 181(3): 1806 - 1813. [Abstract] [Full Text] [PDF]

				J. A. Williams, J. M. Lumsden, X. Yu, L. Feigenbaum, J. Zhang, S. M. Steinberg, and R. J. Hodes Regulation of Thymic NKT Cell Development by the B7-CD28 Costimulatory Pathway J. Immunol., July 15, 2008; 181(2): 907 - 917. [Abstract] [Full Text] [PDF]

				C. Scotta, M. Soligo, C. Camperio, and E. Piccolella FOXP3 Induced by CD28/B7 Interaction Regulates CD25 and Anergic Phenotype in Human CD4+CD25- T Lymphocytes J. Immunol., July 15, 2008; 181(2): 1025 - 1033. [Abstract] [Full Text] [PDF]

				C. Meagher, Q. Tang, B. T. Fife, H. Bour-Jordan, J. Wu, C. Pardoux, M. Bi, K. Melli, and J. A. Bluestone Spontaneous Development of a Pancreatic Exocrine Disease in CD28-Deficient NOD Mice J. Immunol., June 15, 2008; 180(12): 7793 - 7803. [Abstract] [Full Text] [PDF]

				J. Kang, S. J. Huddleston, J. M. Fraser, and A. Khoruts De novo induction of antigen-specific CD4+CD25+Foxp3+ regulatory T cells in vivo following systemic antigen administration accompanied by blockade of mTOR J. Leukoc. Biol., May 1, 2008; 83(5): 1230 - 1239. [Abstract] [Full Text] [PDF]

				P. J. Spence and E. A. Green Foxp3+ regulatory T cells promiscuously accept thymic signals critical for their development PNAS, January 22, 2008; 105(3): 973 - 978. [Abstract] [Full Text] [PDF]

				Y. Burmeister, T. Lischke, A. C. Dahler, H. W. Mages, K.-P. Lam, A. J. Coyle, R. A. Kroczek, and A. Hutloff ICOS Controls the Pool Size of Effector-Memory and Regulatory T Cells J. Immunol., January 15, 2008; 180(2): 774 - 782. [Abstract] [Full Text] [PDF]

				M. Tritt, E. Sgouroudis, E. d'Hennezel, A. Albanese, and C. A. Piccirillo Functional Waning of Naturally Occurring CD4+ Regulatory T-Cells Contributes to the Onset of Autoimmune Diabetes Diabetes, January 1, 2008; 57(1): 113 - 123. [Abstract] [Full Text] [PDF]

				B. P. Iliopoulou, J. Alroy, and B. T. Huber CD28 Deficiency Exacerbates Joint Inflammation upon Borrelia burgdorferi Infection, Resulting in the Development of Chronic Lyme Arthritis J. Immunol., December 15, 2007; 179(12): 8076 - 8082. [Abstract] [Full Text] [PDF]

				C. Guillonneau, C. Seveno, A.-S. Dugast, X.-L. Li, K. Renaudin, F. Haspot, C. Usal, J. Veziers, I. Anegon, and B. Vanhove Anti-CD28 Antibodies Modify Regulatory Mechanisms and Reinforce Tolerance in CD40Ig-Treated Heart Allograft Recipients J. Immunol., December 15, 2007; 179(12): 8164 - 8171. [Abstract] [Full Text] [PDF]

				J.-R. Pallandre, E. Brillard, G. Crehange, A. Radlovic, J.-P. Remy-Martin, P. Saas, P.-S. Rohrlich, X. Pivot, X. Ling, P. Tiberghien, et al. Role of STAT3 in CD4+CD25+FOXP3+ Regulatory Lymphocyte Generation: Implications in Graft-versus-Host Disease and Antitumor Immunity J. Immunol., December 1, 2007; 179(11): 7593 - 7604. [Abstract] [Full Text] [PDF]

				M. D. Vu, X. Xiao, W. Gao, N. Degauque, M. Chen, A. Kroemer, N. Killeen, N. Ishii, and X. Chang Li OX40 costimulation turns off Foxp3+ Tregs Blood, October 1, 2007; 110(7): 2501 - 2510. [Abstract] [Full Text] [PDF]

				E. Marks, M. Verolin, A. Stensson, and N. Lycke Differential CD28 and Inducible Costimulatory Molecule Signaling Requirements for Protective CD4+ T-Cell-Mediated Immunity against Genital Tract Chlamydia trachomatis Infection Infect. Immun., September 1, 2007; 75(9): 4638 - 4647. [Abstract] [Full Text] [PDF]

				L. E. Pereira, F. Villinger, N. Onlamoon, P. Bryan, A. Cardona, K. Pattanapanysat, K. Mori, S. Hagen, L. Picker, and A. A. Ansari Simian Immunodeficiency Virus (SIV) Infection Influences the Level and Function of Regulatory T Cells in SIV-Infected Rhesus Macaques but Not SIV-Infected Sooty Mangabeys J. Virol., May 1, 2007; 81(9): 4445 - 4456. [Abstract] [Full Text] [PDF]

				Y. Zhan, D. Bourges, J. A. Dromey, L. C. Harrison, and A. M. Lew The origin of thymic CD4+CD25+ regulatory T cells and their co-stimulatory requirements are determined after elimination of recirculating peripheral CD4+ cells Int. Immunol., April 1, 2007; 19(4): 455 - 463. [Abstract] [Full Text] [PDF]

				A. L. Bayer, A. Yu, and T. R. Malek Function of the IL-2R for Thymic and Peripheral CD4+CD25+ Foxp3+ T Regulatory Cells J. Immunol., April 1, 2007; 178(7): 4062 - 4071. [Abstract] [Full Text] [PDF]

				M. K. Mann, K. Maresz, L. P. Shriver, Y. Tan, and B. N. Dittel B Cell Regulation of CD4+CD25+ T Regulatory Cells and IL-10 Via B7 is Essential for Recovery From Experimental Autoimmune Encephalomyelitis J. Immunol., March 15, 2007; 178(6): 3447 - 3456. [Abstract] [Full Text] [PDF]

				M. H. Maillard, V. Cotta-de-Almeida, F. Takeshima, D. D. Nguyen, P. Michetti, C. Nagler, A. K. Bhan, and S. B. Snapper The Wiskott-Aldrich syndrome protein is required for the function of CD4+CD25+Foxp3+ regulatory T cells J. Exp. Med., February 19, 2007; 204(2): 381 - 391. [Abstract] [Full Text] [PDF]

				D. T. Patton, O. A. Garden, W. P. Pearce, L. E. Clough, C. R. Monk, E. Leung, W. C. Rowan, S. Sancho, L. S. K. Walker, B. Vanhaesebroeck, et al. Cutting Edge: The Phosphoinositide 3-Kinase p110{delta} Is Critical for the Function of CD4+CD25+Foxp3+ Regulatory T Cells J. Immunol., November 15, 2006; 177(10): 6598 - 6602. [Abstract] [Full Text] [PDF]

				B. Fritzsching, N. Oberle, E. Pauly, R. Geffers, J. Buer, J. Poschl, P. Krammer, O. Linderkamp, and E. Suri-Payer Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death Blood, November 15, 2006; 108(10): 3371 - 3378. [Abstract] [Full Text] [PDF]

				S. Read, R. Greenwald, A. Izcue, N. Robinson, D. Mandelbrot, L. Francisco, A. H. Sharpe, and F. Powrie Blockade of CTLA-4 on CD4+CD25+ Regulatory T Cells Abrogates Their Function In Vivo J. Immunol., October 1, 2006; 177(7): 4376 - 4383. [Abstract] [Full Text] [PDF]

				S. Pejawar-Gaddy and M. A. Alexander-Miller Ligation of CD80 Is Critical for High-Level CD25 Expression on CD8+ T Lymphocytes J. Immunol., October 1, 2006; 177(7): 4495 - 4502. [Abstract] [Full Text] [PDF]

				A. Toda and C. A. Piccirillo Development and function of naturally occurring CD4+CD25+ regulatory T cells J. Leukoc. Biol., September 1, 2006; 80(3): 458 - 470. [Abstract] [Full Text] [PDF]

				J. J. Engelhardt, T. J. Sullivan, and J. P. Allison CTLA-4 Overexpression Inhibits T Cell Responses through a CD28-B7-Dependent Mechanism J. Immunol., July 15, 2006; 177(2): 1052 - 1061. [Abstract] [Full Text] [PDF]

				R. Yang, Z. Cai, Y. Zhang, W. H. Yutzy IV, K. F. Roby, and R. B.S. Roden CD80 in Immune Suppression by Mouse Ovarian Carcinoma-Associated Gr-1+CD11b+ Myeloid Cells. Cancer Res., July 1, 2006; 66(13): 6807 - 6815. [Abstract] [Full Text] [PDF]

				P. Alard, J. N. Manirarora, S. A. Parnell, J. L. Hudkins, S. L. Clark, and M. M. Kosiewicz Deficiency in NOD Antigen-Presenting Cell Function May Be Responsible for Suboptimal CD4+CD25+ T-Cell-Mediated Regulation and Type 1 Diabetes Development in NOD Mice. Diabetes, July 1, 2006; 55(7): 2098 - 2105. [Abstract] [Full Text] [PDF]

				N. Legrand, T. Cupedo, A. U. van Lent, M. J. Ebeli, K. Weijer, T. Hanke, and H. Spits Transient accumulation of human mature thymocytes and regulatory T cells with CD28 superagonist in "human immune system" Rag2-/-{gamma}c-/- mice Blood, July 1, 2006; 108(1): 238 - 245. [Abstract] [Full Text] [PDF]

				J. J. A. Coenen, H. J. P. M. Koenen, E. van Rijssen, L. Boon, I. Joosten, and L. B. Hilbrands CTLA-4 Engagement and Regulatory CD4+CD25+ T Cells Independently Control CD8+-Mediated Responses under Costimulation Blockade J. Immunol., May 1, 2006; 176(9): 5240 - 5246. [Abstract] [Full Text] [PDF]

				C. Lyddane, B. U. Gajewska, E. Santos, P. D. King, G. C. Furtado, and M. Sadelain Cutting Edge: CD28 Controls Dominant Regulatory T Cell Activity during Active Immunization J. Immunol., March 15, 2006; 176(6): 3306 - 3310. [Abstract] [Full Text] [PDF]

				S. Koonpaew, S. Shen, L. Flowers, and W. Zhang LAT-mediated signaling in CD4+CD25+ regulatory T cell development J. Exp. Med., January 23, 2006; 203(1): 119 - 129. [Abstract] [Full Text] [PDF]

				M. Delgado, A. Chorny, E. Gonzalez-Rey, and D. Ganea Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo J. Leukoc. Biol., December 1, 2005; 78(6): 1327 - 1338. [Abstract] [Full Text] [PDF]

				D. K. Sojka, A. Hughson, T. L. Sukiennicki, and D. J. Fowell Early Kinetic Window of Target T Cell Susceptibility to CD25+ Regulatory T Cell Activity J. Immunol., December 1, 2005; 175(11): 7274 - 7280. [Abstract] [Full Text] [PDF]

				P. H. Tan, J. B. Yates, S.-A. Xue, C. Chan, W. J. Jordan, J. E. Harper, M. P. Watson, R. Dong, M. A. Ritter, R. I. Lechler, et al. Creation of tolerogenic human dendritic cells via intracellular CTLA4: a novel strategy with potential in clinical immunosuppression Blood, November 1, 2005; 106(9): 2936 - 2943. [Abstract] [Full Text] [PDF]

				N Beyersdorf, T Hanke, T Kerkau, and T Hunig Superagonistic anti-CD28 antibodies: potent activators of regulatory T cells for the therapy of autoimmune diseases Ann Rheum Dis, November 1, 2005; 64(suppl_4): iv91 - iv95. [Abstract] [Full Text] [PDF]

				S. M Metcalfe Axotrophin and leukaemia inhibitory factor (LIF) in transplantation tolerance Phil Trans R Soc B, September 29, 2005; 360(1461): 1687 - 1694. [Abstract] [Full Text] [PDF]

				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]

				E. L. Masteller, M. R. Warner, Q. Tang, K. V. Tarbell, H. McDevitt, and J. A. Bluestone Expansion of Functional Endogenous Antigen-Specific CD4+CD25+ Regulatory T Cells from Nonobese Diabetic Mice J. Immunol., September 1, 2005; 175(5): 3053 - 3059. [Abstract] [Full Text] [PDF]

				N. Beyersdorf, S. Gaupp, K. Balbach, J. Schmidt, K. V. Toyka, C.-H. Lin, T. Hanke, T. Hunig, T. Kerkau, and R. Gold Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis J. Exp. Med., August 1, 2005; 202(3): 445 - 455. [Abstract] [Full Text] [PDF]

				L.-F. Lu, D. C. Gondek, Z. A. Scott, and R. J. Noelle NF{kappa}B-Inducing Kinase Deficiency Results in the Development of a Subset of Regulatory T Cells, which Shows a Hyperproliferative Activity upon Glucocorticoid-Induced TNF Receptor Family-Related Gene Stimulation J. Immunol., August 1, 2005; 175(3): 1651 - 1657. [Abstract] [Full Text] [PDF]

				H. Shao, Y. Peng, T. Liao, M. Wang, M. Song, H. J. Kaplan, and D. Sun A Shared Epitope of the Interphotoreceptor Retinoid-Binding Protein Recognized by the CD4+ and CD8+ Autoreactive T Cells J. Immunol., August 1, 2005; 175(3): 1851 - 1857. [Abstract] [Full Text] [PDF]

				G. Darrasse-Jeze, G. Marodon, B. L. Salomon, M. Catala, and D. Klatzmann Ontogeny of CD4+CD25+ regulatory/suppressor T cells in human fetuses Blood, June 15, 2005; 105(12): 4715 - 4721. [Abstract] [Full Text] [PDF]

				K. Loser, A. Scherer, M. B. W. Krummen, G. Varga, T. Higuchi, T. Schwarz, A. H. Sharpe, S. Grabbe, J. A. Bluestone, and S. Beissert An Important Role of CD80/CD86-CTLA-4 Signaling during Photocarcinogenesis in Mice J. Immunol., May 1, 2005; 174(9): 5298 - 5305. [Abstract] [Full Text] [PDF]

				K. M. Thorstenson, L. Herzovi, and A. Khoruts A model of suppression of the antigen-specific CD4 T cell response by regulatory CD25+CD4 T cells in vivo Int. Immunol., April 1, 2005; 17(4): 335 - 342. [Abstract] [Full Text] [PDF]

				H. Kataoka, S. Takahashi, K. Takase, S. Yamasaki, T. Yokosuka, T. Koike, and T. Saito CD25+CD4+ regulatory T cells exert in vitro suppressive activity independent of CTLA-4 Int. Immunol., April 1, 2005; 17(4): 421 - 427. [Abstract] [Full Text] [PDF]

				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]

				S. Liang, P. Alard, Y. Zhao, S. Parnell, S. L. Clark, and M. M. Kosiewicz Conversion of CD4+ CD25- cells into CD4+ CD25+ regulatory T cells in vivo requires B7 costimulation, but not the thymus J. Exp. Med., January 3, 2005; 201(1): 127 - 137. [Abstract] [Full Text] [PDF]

				J. L. Riley and C. H. June The CD28 family: a T-cell rheostat for therapeutic control of T-cell activation Blood, January 1, 2005; 105(1): 13 - 21. [Abstract] [Full Text] [PDF]

				G. L. Stephens, R. S. McHugh, M. J. Whitters, D. A. Young, D. Luxenberg, B. M. Carreno, M. Collins, and E. M. Shevach Engagement of Glucocorticoid-Induced TNFR Family-Related Receptor on Effector T Cells by its Ligand Mediates Resistance to Suppression by CD4+CD25+ T Cells J. Immunol., October 15, 2004; 173(8): 5008 - 5020. [Abstract] [Full Text] [PDF]

				J. Lohr, B. Knoechel, E. C. Kahn, and A. K. Abbas Role of B7 in T Cell Tolerance J. Immunol., October 15, 2004; 173(8): 5028 - 5035. [Abstract] [Full Text] [PDF]

				J. A. Bluestone and Q. Tang Therapeutic vaccination using CD4+CD25+ antigen-specific regulatory T cells PNAS, October 5, 2004; 101(suppl_2): 14622 - 14626. [Abstract] [Full Text] [PDF]

				J. Machen, J. Harnaha, R. Lakomy, A. Styche, M. Trucco, and N. Giannoukakis Antisense Oligonucleotides Down-Regulating Costimulation Confer Diabetes-Preventive Properties to Nonobese Diabetic Mouse Dendritic Cells J. Immunol., October 1, 2004; 173(7): 4331 - 4341. [Abstract] [Full Text] [PDF]

				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]

				G. Zheng, B. Wang, and A. Chen The 4-1BB Costimulation Augments the Proliferation of CD4+CD25+ Regulatory T Cells J. Immunol., August 15, 2004; 173(4): 2428 - 2434. [Abstract] [Full Text] [PDF]

				H. Shao, S. L. Sun, H. J. Kaplan, and D. Sun Characterization of Rat CD8+ Uveitogenic T Cells Specific for Interphotoreceptor Retinal-Binding Protein 1177-1191 J. Immunol., August 15, 2004; 173(4): 2849 - 2854. [Abstract] [Full Text] [PDF]

				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]

				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]

				E. A. Wohlfert, M. K. Callahan, and R. B. Clark Resistance to CD4+CD25+ Regulatory T Cells and TGF-{beta} in Cbl-b-/- Mice J. Immunol., July 15, 2004; 173(2): 1059 - 1065. [Abstract] [Full Text] [PDF]

				M. Mamura, W. Lee, T. J. Sullivan, A. Felici, A. L. Sowers, J. P. Allison, and J. J. Letterio CD28 disruption exacerbates inflammation in Tgf-{beta}1-/- mice: in vivo suppression by CD4+CD25+ regulatory T cells independent of autocrine TGF-{beta}1 Blood, June 15, 2004; 103(12): 4594 - 4601. [Abstract] [Full Text] [PDF]

				Q. Tang, K. J. Henriksen, M. Bi, E. B. Finger, G. Szot, J. Ye, E. L. Masteller, H. McDevitt, M. Bonyhadi, and J. A. Bluestone In Vitro-expanded Antigen-specific Regulatory T Cells Suppress Autoimmune Diabetes J. Exp. Med., June 7, 2004; 199(11): 1455 - 1465. [Abstract] [Full Text] [PDF]

				A. M. Thornton, E. E. Donovan, C. A. Piccirillo, and E. M. Shevach Cutting Edge: IL-2 Is Critically Required for the In Vitro Activation of CD4+CD25+ T Cell Suppressor Function J. Immunol., June 1, 2004; 172(11): 6519 - 6523. [Abstract] [Full Text] [PDF]

				H.-b. Ji, G. Liao, W. A. Faubion, A. C. Abadia-Molina, C. Cozzo, F. S. Laroux, A. Caton, and C. Terhorst Cutting Edge: The Natural Ligand for Glucocorticoid-Induced TNF Receptor-Related Protein Abrogates Regulatory T Cell Suppression J. Immunol., May 15, 2004; 172(10): 5823 - 5827. [Abstract] [Full Text] [PDF]

				J. Vermeiren, J. L. Ceuppens, M. Van Ghelue, P. Witters, D. Bullens, H. W. Mages, R. A. Kroczek, and S. W. Van Gool Human T Cell Activation by Costimulatory Signal-Deficient Allogeneic Cells Induces Inducible Costimulator-Expressing Anergic T Cells with Regulatory Cell Activity J. Immunol., May 1, 2004; 172(9): 5371 - 5378. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tang, Q. Articles by Bluestone, J. A. Search for Related Content PubMed PubMed Citation Articles by Tang, Q. Articles by Bluestone, J. A.