The JI
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     
 

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gandhi, R.
Right arrow Articles by Weiner, H. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gandhi, R.
Right arrow Articles by Weiner, H. L.
The Journal of Immunology, 2007, 178: 4017-4021.
Copyright © 2007 by The American Association of Immunologists, Inc.

CUTTING EDGE

Cutting Edge: Immature Human Dendritic Cells Express Latency-Associated Peptide and Inhibit T Cell Activation in a TGF-beta-Dependent Manner1

Roopali Gandhi, David E. Anderson and Howard L. Weiner2

Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Dendritic cells (DCs) play a critical role in both initiating immune responses and in maintaining peripheral tolerance. However, the exact mechanism by which DCs instruct/influence the generation of effector vs regulatory T cells is not clear. In this study, we present evidence that TGF-beta, an important immunoregulatory molecule, is present on the surface of ex vivo immature human DCs bound by latency-associated peptide (LAP). Maturation of DCs upon stimulation with LPS results in loss of membrane-bound LAP and up-regulation of HLA class II and costimulatory molecules. The presence of LAP on immature DCs selectively inhibits Th1 cell but not Th17 cell differentiation and is required for differentiation and/or survival of Foxp3-positive regulatory T cells. Taken together, our results indicate that surface expression of TGF-beta on DCs in association with LAP is one of the mechanisms by which immature DCs limit T cell activation and thus prevent autoimmune responses.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Dendritic cells (DCs)3 are bone marrow-derived APCs that have a major role in initiating immune responses by activation of naive T cells (1) and in maintaining T cell tolerance, and thus modulate homeostasis and prevention of autoimmunity (2, 3, 4). Under steady-state conditions, DCs maintain an immature status until an inflammatory signal promotes their activation, at which time they up-regulate costimulatory markers such as CD80, CD83, CD86, and CD40 and facilitate T cell activation and expansion (5). Immature DCs can influence tolerance by inducing anergic/regulatory T cells (Tregs) both in vitro (4, 6, 7) and in vivo (8, 9). They can facilitate expansion of Tregs in the presence of IL-2 (10), and human monocyte-derived immature DCs can induce IL-10-producing Tregs (11).

TGF-beta maintains T cell tolerance by regulating lymphocyte proliferation and/or T cell differentiation (12, 13, 14, 15). In addition, in the presence of TCR signaling, TGF-beta can induce generation of CD25+ Tregs from peripheral CD25– T cells (16). TGF-beta is secreted in its latent form as a homodimer and is noncovalently associated with a homodimer of latency-associated peptide (LAP) (12). Expression of surface bound TGF-beta in association with LAP on CD4+ T cells is important in mediating contact-dependent suppression (17). We have found that expression of surface-bound TGF-beta on CD4+ CD25– cells can suppress two experimental autoimmune diseases, colitis and experimental autoimmune encephalomyelitis (18, 19), suggesting that surface-bound TGF-beta has immunoregulatory function in both CD25+ and CD25– T cell subpopulations.

Given the importance of TGF-beta in T cell regulation and the pivotal role of immature DCs in T cell tolerance, we investigated the expression and functional significance of surface-bound TGF-beta on human ex vivo immature DCs. We found that immature DCs express cell surface-bound TGF-beta associated with LAP and that its expression regulates both naive Th1 cell differentiation and effector T cell activation, in addition to influencing differentiation and/or survival of CD4+CD25+Foxp3+ Tregs.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Disclosures
 References
 
Culture medium and reagents

Cells were cultured in X-VIVO-15 medium (Cambrex) supplemented with 1% human serum (BioWhittaker). Anti-TGF-beta Ab, Ab isotype controls, and rLAP were obtained from R&D Systems. Fluorescein-conjugated Lin Abs and allophycocyanin-conjugated CD11c Abs were used to identify myeloid DCs (mDCs) in concert with PE-labeled mAbs to HLA-DR, CD80, CD83, and CD86. CD4-FITC, CD25-APC and IFN-{gamma}-PE Abs (BD Pharmingen) were used for sorting and/or analysis. Foxp3-PE and IL-17-PE Abs were purchased from eBioscience. Anti-CD123-FITC Ab was obtained from Miltenyi Biotec. Real-time primers, probes, RT-PCR kit, and PCR mix were obtained from Applied Biosystems.

Coculture assays

DCs and naive or total CD4+ T cells were isolated from PBMCs using total blood DC, naive CD4+ T cell, and CD4+ T cell magnetic bead isolation kits, respectively (Miltenyi Biotec). Purified DCs and T cells were >90–93% positive as assessed by FACS analysis. T cells were differentiated with DCs for 7 days at a 10:1 ratio. In small interfering RNA (siRNA) experiments, naive CD4+ T cells were transfected with two different, validated, siRNA constructs that target TGF-beta1 as well as a negative control construct (Ambion) using the Amaxa system. Transfected T cells were left overnight in medium according to the manufacturer’s recommendations, before coculture with freshly isolated, unmanipulated DCs. After coculture, differentiated T cells were negatively selected using magnetic beads and were restimulated with plate-bound anti-CD3 with or without 1 µg/ml soluble anti-CD28 for 24 h (intracellular staining) or for 5 days to determine proliferation and cytokines secreted by differentiated T cells. IFN-{gamma}, IL-6, IL-4, IL-2, and TNF-{alpha} were determined using the Th1/T2 cytokine bead array (BD Biosciences). Frequencies of cells secreting IFN-{gamma} or IL-17 were determined using a Cytofix/Cytoperm kit (BD Pharmingen). The proportion of effector and Tregs after coculture were determined by first staining with anti-CD4 and anti-CD25 mAb, followed by fixation/permeabilization and staining with Foxp3-specific mAb (eBioscience). Statistical analysis used paired t tests using Prism software.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
LAP expression on ex vivo DCs

To determine the significance of TGF-beta in immature DC induced tolerance, we investigated the expression of LAP on human ex vivo mDCs and plasmacytoid DCs (pDCs) by multiparametric flow cytometric analysis (Fig. 1). The mDC subpopulation was defined as CD11c bright and Lin– as previously reported (20), and these cells uniformly expressed LAP on their cell surface in the resting/steady state (Fig. 1A). Staining of pDCs, which were gated as CD11c–CD123+, demonstrated that many but not all pDCs also expressed LAP (Fig. 1B). The frequency and intensity of LAP expression among mDCs was consistent among many individuals examined (Fig. 1C).


Figure 1
View larger version (34K):
[in this window]
[in a new window]

  		FIGURE 1. Expression of LAP on DC subpopulations. Total PBMCs were stained with anti-LAP (empty histogram) or isotype control (IC, shaded histogram) Abs. A, mDCs were gated as CD11c+ and Lin– cells. B, pDCs were gated as CD123+ and CD11c– cells. C, Mean fluorescence intensities (MFI) of LAP staining and percentages of LAP+ mDCs in six healthy individuals is shown.

 
Loss of LAP expression on LPS-activated DCs

As activation of DCs leads to T cell immunity with concomitant loss of tolerogenic properties (21), we evaluated whether activation of DCs had any effect on expression of LAP. We found that LPS activated DCs (20 h) lose surface expression of LAP, and that its loss correlates with up-regulation of costimulatory molecules CD40, CD80, CD83, CD86, and HLA-DR (Fig. 2). We postulate that loss of LAP expression in association with up-regulation of costimulatory molecules is a critical step in the transition of tolerogenic DCs into immunogenic DCs. These results are consistent with previous reports suggesting that murine immature bone marrow-derived DCs express more TGF-beta than mature DCs both at protein and mRNA levels (22).


Figure 2
View larger version (23K):
[in this window]
[in a new window]

  		FIGURE 2. Loss of LAP expression after activation of DCs. Purified DCs were activated with 1 µg/ml LPS for 20 h. A, LAP staining on ex vivo DCs (blue profile), LPS-activated DCs (red profile), and isotype control (filled gray profile). B, The phenotype of mature DC was established by staining for activation and costimulatory molecules. Down-modulation of LAP correlated with up-modulation of activation and costimulatory molecules.

 
TGF-beta neutralization on immature DCs leads to increased proliferation and enhanced IFN-{gamma} in primary T cell coculture

To directly test our hypothesis that surface TGF-beta expression on immature DCs limits T cell activation, we performed MLR experiments. We used either anti-TGF-beta Ab or rLAP to neutralize TGF-beta on DCs during a primary MLR with naive T cells. rLAP binds to active TGF-beta with very high affinity, and thus serves as an efficient TGF-beta-neutralizing agent (23). We found that addition of rLAP in primary culture led to enhanced T cell proliferation and increased IFN-{gamma}, TNF-{alpha}, and IL-6 production (Fig. 3, A–C). We were unable to detect secretion of TGF-beta in primary cultures. Addition of rLAP to naive T cells alone had no effect on their proliferation or cytokine secretion. Similar results were obtained using two anti-TGF-beta Abs in MLR, indicating that addition of rLAP to the MLR was indeed neutralizing TGF-beta activity on immature DCs rather than acting as a T cell mitogen (Fig. 3D).


Figure 3
View larger version (46K):
[in this window]
[in a new window]

  		FIGURE 3. TGF-beta neutralization on DCs leads to increased proliferation and enhanced IFN-{gamma} in primary coculture. Purified total DCs were cultured with allogeneic CD4+ T cells at the ratio of 1:10 in the presence or absence of 5 µg/ml rLAP or anti-TGF-beta Abs (10 µg/ml). A, T cell proliferation was determined after 5 days of culture by thymidine incorporation. IFN-{gamma} (B), IL-6, and TNF-{alpha} (C) levels were determined after 5 days of culture using cytokine bead array. D, T cell proliferation was assessed in the presence of mouse monoclonal and rabbit polyclonal TGF-beta Abs and their respective isotype controls (IC) or in the absence (MLR) or presence of rLAP (MLR + rLAP). E, CFSE dilution of naive (CD25–), effector (CD25int), and regulatory (CD25high) T cell subpopulations in the presence or absence of TGF-beta neutralization with rLAP was evaluated after 5 days. Results are representative of three independent experiments. Error bars represent SD among replicate wells.

 
In humans, a Treg population is defined by high expression of CD25 (CD25high), which is functionally similar to CD25+ Tregs in murine systems (24). To determine whether the presence of TGF-beta on immature DCs influenced a particular T cell subset, regulatory (CD25high), effector (CD25int) and resting (CD25–) CD4+ T cells were isolated by FACS and cultured with allogeneic immature ex vivo DCs in the presence or absence of rLAP. After 5 days of culture, neutralization of surface TGF-beta with rLAP increased the proliferation of effector as well as of resting/naive T cell subsets but did not appear to influence the proliferation of Tregs (Fig. 3E). Thus, surface expression of TGF-beta on immature DCs limits activation of naive and effector T cell populations.

Surface TGF-beta neutralization on DCs leads to increased Th1 polarization of T cells during T cell differentiation

To investigate the effect of immature DC surface expression of TGF-beta on naive T cell differentiation, immature DCs were cultured with allogeneic naive T cells in the presence or absence of rLAP. After 7 days of differentiation, T cells were isolated by negative selection and restimulated with graded doses of anti-CD3 Ab in the presence or absence of costimulation provided by anti-CD28 Ab. In the absence of costimulation, neutralization of TGF-beta during naive T cell differentiation enhanced the proliferation and the frequency of IFN-{gamma}-positive T cells (Fig. 4, A and B), whereas in the presence of anti-CD28 Ab there was no enhancement of proliferation and only minimal enhancement of IFN-{gamma}-positive T cells (Fig. 4, C and D). Thus, T cells differentiated in the presence of TGF-beta neutralization were more responsive to TCR stimulation and relatively costimulation independent. T cells differentiated with TGF-beta neutralization secreted increased levels of IFN-{gamma}, TNF-{alpha}, IL-4, IL-6, and IL-10 cytokines (Fig. 4E), though the actual amount of IFN-{gamma} was significantly higher (~1000-fold) than amounts of Th2-associated IL-4. To determine the degree of Th1/Th2 differentiation in the presence of TGF-beta neutralization, T-bet (Th1) and GATA3 (Th2) transcription factors were measured using real-time PCR. We found increased levels of T-bet (TBX) in T cells that were differentiated in the presence of TGF-beta neutralization, whereas no differences were observed in the levels of GATA3 after 7 days of differentiation culture (Fig. 4F).


Figure 4
View larger version (31K):
[in this window]
[in a new window]

  		FIGURE 4. LAP neutralization on DCs led to increased Th1 polarization of T cells during T cell differentiation. Naive T cells were primed with purified allogeneic DCs at a ratio of 10:1 in the presence or absence of 5 µg/ml rLAP. Primed T cells were purified by negative selection using magnetic beads and were restimulated with plate-bound anti-CD3 alone (A) or with soluble anti-CD28 (C) for 5 days to determine proliferation. IFN-{gamma}-positive cells were determined after 24 h of stimulation with plate bound anti-CD3 alone (B) or with soluble anti-CD28 (D). One representative of seven independent experiments is shown. Increased frequency of IFN-{gamma}-positive cells was observed with rLAP in all seven experiments. E, Th1/Th2 cytokines secreted by differentiated T cells restimulated with anti-CD3/CD28 mAbs. Value of IFN-{gamma} secreted is shown on left y-axis, whereas TNF-{alpha}, IL-10, IL-4, and IL-6 are depicted on right y-axis. F, Relative expression levels of Th1 (T-bet) or Th2 (GATA3) transcription factors in differentiated T cells were determined by real-time PCR. G, TGF-beta mRNA was inhibited in naive T cells using two different siRNA oligonucleotides (60 and 78% inhibition, respectively, compared with negative control siRNA) before coculture with allogeneic immature DCs in the presence or absence of rLAP. After 7 days of differentiation, primed T cells were repurified and stimulated with plate-bound anti-CD3 mAb to determine the frequencies of IFN-{gamma}+ T cells. Error bars reflect SD among replicate wells.

 
To further verify that the effects of TGF-beta neutralization were related to LAP expression on immature DCs, the following experiments were performed. Staining of human naive T cells ex vivo and after coculture with immature DCs indicated no LAP expression on their cell surface, and stimulation of naive T cells with anti-CD3 in presence or absence of anti-CD28 failed to induce secretion of TGF-beta (data not shown). Finally, we demonstrated that addition of rLAP had comparable effects in coculture assays even when TGF-beta mRNA expression was inhibited in naive ex vivo human T cells using siRNA (Fig. 4G).

Surface TGF-beta on immature DCs preferentially influences Th1 cell differentiation

Foxp3 has been identified as a specific Treg marker, and Foxp3 gene transfer into naive T cells can impart a Treg phenotype to T cells (25). In mice, TGF-beta has been shown to be essential to maintain Foxp3 expression and Treg function (26). In addition to Th1 and Th2 subsets of T cells, another subset of IL-17-producing T cells (Th17) has been identified, which plays a major role during autoimmunity. In mice it has been shown that TGF-beta also plays a role in the differentiation of Th17 cells (27, 28, 29). Accordingly, we investigated the influence of LAP-positive immature DCs on the differentiation of Th1 vs Th17 vs Foxp3 (Tregs) cells. Immature DCs were cultured with allogeneic naive T cells in the presence or absence of rLAP for 7 days. Percentages of IFN-{gamma}-positive, IL-17-positive, and Foxp3 bright populations were then determined by FACS analysis. We found a 3-fold increase in the IFN-{gamma} positive cells (Fig. 5A), but no increase in Th17 cells. In addition, TGF-beta neutralization led to a significant increase in frequencies of effector T cells gated as a CD25intFoxp3int population and a significant decrease of the regulatory CD25highFoxp3bright population (Fig. 5, A and B). Absolute numbers of effector and Tregs mirrored changes in their frequencies, with an average of 5511 ± 1311 effector and 584 ± 105 regulatory cells in the absence of LAP and 6772 ± 1412 effector and 349 ± 69 regulatory cells in the presence of LAP. Given that we began these assays with naive T cells lacking CD25high cells, we believe these data indicate that surface TGF-beta present on immature DCs plays a role in human Treg differentiation, rather than expansion (Fig. 3E) or survival. The extent to which surface TGF-beta present on immature DCs influences differentiation of human Th17 cells, as has been demonstrated in murine systems (30), needs to be examined further.


Figure 5
View larger version (34K):
[in this window]
[in a new window]

  		FIGURE 5. Surface TGF-beta on immature DCs preferentially influences Th1 cell differentiation. Naive T cells were differentiated with immature DCs in the presence (right panels) or absence (left panels) of TGF-beta neutralization with rLAP. A, Differentiated T cells were repurified from coculture and analyzed to determine differentiation of Th1 (IFN-{gamma}+) vs Th17 (IL-17+) vs Treg (CD25highFoxp3bright) populations. B, Results of six independent differentiation experiments demonstrated significantly decreased percentages of CD25highFoxp3bright populations and increased CD25intFoxp3int populations.

 
In conclusion, DCs have both positive and negative effects on T cell immunity, although the characteristics of DCs that confer these properties are not completely understood. We have discovered that immature DCs express cell surface bound TGF-beta, which is lost following activation and markedly affects the functional properties of DCs in T cell activation. TGF-beta is known to play a central role in orchestrating immune responses (12, 13, 14, 15). Thus, activation or maturation of DCs is associated with loss of surface bound TGF-beta, which serves to enhance Th1 differentiation, while simultaneously inhibiting the differentiation/survival of regulatory CD25+ Tregs. This suggests that the presence of TGF-beta on DCs serves as a tolerogenic or inhibitory effect on the immune system. In future studies, it will be important to determine the implications of surface bound TGF-beta on DCs in autoimmune diseases such as multiple sclerosis and type 1 diabetes.


   Acknowledgments
 
We thank Dr. Vijay Kuchroo for suggestions during manuscript preparation.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by National Institutes of Health Grant NS23132. Back

2 Address correspondence and reprint requests to Dr. Howard L. Weiner, Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115. E-mail address: hweiner{at}rics.bwh.harvard.edu Back

3 Abbreviations used in this paper: DC, dendritic cell; LAP, latency-associated peptide; mDC, myeloid DC; pDC, plasmacytoid DC; Treg, regulatory T cell; siRNA, small interfering RNA; int, intermediate. Back

Received for publication September 27, 2006. Accepted for publication January 31, 2007.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 

  1. Lanzavecchia, A., F. Sallusto. 2001. Regulation of T cell immunity by dendritic cells. Cell 106: 263-266. [Medline]
  2. Banchereau, J., R. M. Steinman. 1998. Dendritic cells and the control of immunity. Nature 392: 245-252. [Medline]
  3. Mellman, I., R. M. Steinman. 2001. Dendritic cells: specialized and regulated antigen processing machines. Cell 106: 255-258. [Medline]
  4. Steinman, R. M., D. Hawiger, M. C. Nussenzweig. 2003. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21: 685-711. [Medline]
  5. Fujii, S., K. Liu, C. Smith, A. J. Bonito, R. M. Steinman. 2004. The linkage of innate to adaptive immunity via maturing dendritic cells in vivo requires CD40 ligation in addition to antigen presentation and CD80/86 costimulation. J. Exp. Med. 199: 1607-1618. [Abstract/Free Full Text]
  6. Roncarolo, M. G., M. K. Levings, C. Traversari. 2001. Differentiation of T regulatory cells by immature dendritic cells. J. Exp. Med. 193: F5-F9. [Free Full Text]
  7. Mahnke, K., E. Schmitt, L. Bonifaz, A. H. Enk, H. Jonuleit. 2002. Immature, but not inactive: the tolerogenic function of immature dendritic cells. Immunol. Cell Biol. 80: 477-483. [Medline]
  8. Hawiger, D., K. Inaba, Y. Dorsett, M. Guo, K. Mahnke, M. Rivera, J. V. Ravetch, R. M. Steinman, M. C. Nussenzweig. 2001. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J. Exp. Med. 194: 769-779. [Abstract/Free Full Text]
  9. Bonifaz, L., D. Bonnyay, K. Mahnke, M. Rivera, M. C. Nussenzweig, R. M. Steinman. 2002. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J. Exp. Med. 196: 1627-1638. [Abstract/Free Full Text]
  10. Yamazaki, S., M. Patel, A. Harper, A. Bonito, H. Fukuyama, M. Pack, K. V. Tarbell, M. Talmor, J. V. Ravetch, K. Inaba, R. M. Steinman. 2006. Effective expansion of alloantigen-specific Foxp3+CD25+CD4+ regulatory T cells by dendritic cells during the mixed leukocyte reaction. Proc. Natl. Acad. Sci. USA 103: 2758-2763. [Abstract/Free Full Text]
  11. Jonuleit, H., E. Schmitt, G. Schuler, J. Knop, A. H. Enk. 2000. Induction of interleukin 10-producing, nonproliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J. Exp. Med. 192: 1213-1222. [Abstract/Free Full Text]
  12. Li, M. O., Y. Y. Wan, S. Sanjabi, A. K. Robertson, R. A. Flavell. 2006. Transforming growth factor-beta regulation of immune responses. Annu. Rev. Immunol. 24: 99-146. [Medline]
  13. Levings, M. K., R. Bacchetta, U. Schulz, M. G. Roncarolo. 2002. The role of IL-10 and TGF-beta in the differentiation and effector function of T regulatory cells. Int. Arch. Allergy Immunol. 129: 263-276. [Medline]
  14. Gorelik, L., P. E. Fields, R. A. Flavell. 2000. Cutting edge: TGF-beta inhibits Th type 2 development through inhibition of GATA-3 expression. J. Immunol. 165: 4773-4777. [Abstract/Free Full Text]
  15. Gorelik, L., S. Constant, R. A. Flavell. 2002. Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J. Exp. Med. 195: 1499-1505. [Abstract/Free Full Text]
  16. Chen, W., W. Jin, N. Hardegen, K. J. Lei, L. Li, N. Marinos, G. McGrady, S. M. Wahl. 2003. Conversion of peripheral CD4+CD25– naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med. 198: 1875-1886. [Abstract/Free Full Text]
  17. Nakamura, K., A. Kitani, W. Strober. 2001. Cell contact-dependent immunosuppression by CD4+CD25+ regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J. Exp. Med. 194: 629-644. [Abstract/Free Full Text]
  18. Oida, T., X. Zhang, M. Goto, S. Hachimura, M. Totsuka, S. Kaminogawa, H. L. Weiner. 2003. CD4+CD25– T cells that express latency-associated peptide on the surface suppress CD4+CD45RB high-induced colitis by a TGF-beta-dependent mechanism. J. Immunol. 170: 2516-2522. [Abstract/Free Full Text]
  19. Ochi, H., M. Abraham, H. Ishikawa, D. Frenkel, K. Yang, A. S. Basso, H. Wu, M. L. Chen, R. Gandhi, A. Miller, et al 2006. Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+CD25–LAP+ T cells. Nat. Med. 12: 627-635. [Medline]
  20. Banchereau, J., F. Briere, C. Caux, J. Davoust, S. Lebecque, Y. J. Liu, B. Pulendran, K. Palucka. 2000. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18: 767-811. [Medline]
  21. Reis e Sousa, C.. 2006. Dendritic cells in a mature age. Nat. Rev. Immunol. 6: 476-483. [Medline]
  22. Morelli, A. E., A. F. Zahorchak, A. T. Larregina, B. L. Colvin, A. J. Logar, T. Takayama, L. D. Falo, A. W. Thomson. 2001. Cytokine production by mouse myeloid dendritic cells in relation to differentiation and terminal maturation induced by lipopolysaccharide or CD40 ligation. Blood 98: 1512-1523. [Abstract/Free Full Text]
  23. Nakamura, K., A. Kitani, I. Fuss, A. Pedersen, N. Harada, H. Nawata, W. Strober. 2004. TGF-beta1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J. Immunol. 172: 834-842. [Abstract/Free Full Text]
  24. Baecher-Allan, C. M., D. A. Hafler. 2005. Functional analysis of highly defined, FACS-isolated populations of human regulatory CD4+CD25+ T cells. Clin. Immunol. 115: 10-18. [Medline]
  25. Hori, S., T. Nomura, S. Sakaguchi. 2003. Control of regulatory T cell development by the transcription factor Foxp3. Science 299: 1057-1061. [Abstract/Free Full Text]
  26. Marie, J. C., J. J. Letterio, M. Gavin, A. Y. Rudensky. 2005. TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J. Exp. Med. 201: 1061-1067. [Abstract/Free Full Text]
  27. Bettelli, E., Y. Carrier, W. Gao, T. Korn, T. B. Strom, M. Oukka, H. L. Weiner, V. K. Kuchroo. 2006. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441: 235-238. [Medline]
  28. Mangan, P. R., L. E. Harrington, D. B. O’Quinn, W. S. Helms, D. C. Bullard, C. O. Elson, R. D. Hatton, S. M. Wahl, T. R. Schoeb, C. T. Weaver. 2006. Transforming growth factor-beta induces development of the TH1 lineage. Nature 441: 231-234. [Medline]
  29. Veldhoen, M., R. J. Hocking, C. J. Atkins, R. M. Locksley, B. Stockinger. 2006. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24: 179-189. [Medline]
  30. Weaver, C. T., L. E. Harrington, P. R. Mangan, M. Gavrieli, K. M. Murphy. 2006. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24: 677-688. [Medline]



This article has been cited by other articles:


Home page
 Proc. Natl. Acad. Sci. USAHome page
J. N. H. Stern, D. B. Keskin, H. Zhang, H. Lv, Z. Kato, and J. L. Strominger
Amino acid copolymer-specific IL-10-secreting regulatory T cells that ameliorate autoimmune diseases in mice
PNAS, April 1, 2008; 105(13): 5172 - 5176.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
E. Billard, J. Dornand, and A. Gross
Brucella suis Prevents Human Dendritic Cell Maturation and Antigen Presentation through Regulation of Tumor Necrosis Factor Alpha Secretion
Infect. Immun., October 1, 2007; 75(10): 4980 - 4989.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
A. Clayton, J. P. Mitchell, J. Court, M. D. Mason, and Z. Tabi
Human Tumor-Derived Exosomes Selectively Impair Lymphocyte Responses to Interleukin-2
Cancer Res., August 1, 2007; 67(15): 7458 - 7466.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gandhi, R.
Right arrow Articles by Weiner, H. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gandhi, R.
Right arrow Articles by Weiner, H. L.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS