Skip to main content

FOXP3 and GARP (LRRC32): the master and its minion

Abstract

The transcription factor FOXP3 is essential for the development and function of CD4+CD25hiFOXP3+ regulatory T (Treg) cells, but also expressed in activated human helper T cells without acquisition of a regulatory phenotype. This comment focuses on glycoprotein-A repetitions predominant (GARP or LRRC32) recently identified as specific marker of activated human Treg cells, which may provide the missing link toward a better molecular definition of the regulatory phenotype.

Reviewers: Dr Jim Di Danto, Dr Benedita Rocha and Dr Werner Solbach.

Introduction

Proposed role of FOXP3 in self-tolerance

The maintenance of self-tolerance involves central and peripheral mechanisms, but the process of thymic negative selection is imperfect. Self-reacting clones that escape central tolerance are kept in check by a variety of peripheral tolerance mechanisms, in which the dominant tolerance exerted by CD4+CD25+ regulatory T (Treg) cells plays an important role. The development and function of Treg cells crucially depends on the forkhead/winged helix transcription factor FOXP3. This dependence is compellingly illustrated by the fact that loss of function of FOXP3 leads to the development of the fatal autoimmune lymphoproliferative disorder IPEX (immunodysregulation, polyendocrinopathy, and enteropathy, X-linked) syndrome [1, 2]. Similarly, loss of function of FoxP3 in mice, either natural (scurfy) or recombinant, results in an analogous immune pathology due to a lack of Treg cells [35]. The dominant role of FOXP3 is further corroborated by the fact that the gain of function induced by ectopic expression in conventional CD4+CD25- helper T (Th) cells leads to the acquisition of suppressor function and the induction of a partial regulatory phenotype in mice and humans [3, 68].

Despite advances in our understanding of Treg-cell lineage commitment and function, gained mainly by the study of FoxP3 knock-out/knock-in mice [4, 5, 911], the dominant role of FOXP3 in the human system and its suitability as a bona fide marker of human Treg cells have been questioned [8, 1214].

Why should Tregcells need more than FOXP3?

The reasoning that more than FOXP3 is necessary for fully explaining the regulatory phenotype in humans is supported by several observations. First, T-cell receptor (TCR) stimulation of CD4+CD25-FOXP3- T cells leads to the induction of FOXP3 without interfering with the expression of effector cytokines such as interleukin-2 and interferon-γ [1517]. Second, the expression of FOXP3 by conventional CD4+CD25- Th cells and even by Th lines and clones does not necessarily indicate the acquisition of suppressor function [8, 12, 1719]. Third, and more specifically, it has recently been found that demethylation of a conserved FOXP3 intronic region may be a better marker for suppressor function than the differential expression of FOXP3 at the mRNA or protein level in Treg and Th cell clones [20]. Fourth, ectopic expression of FOXP3 in human Th cells does not lead to the establishment of a stable regulatory phenotype [8, 12, 21]. Finally, although the enhancement of FOXP3 expression by transforming growth factor-β1 (TGF-β1) in activated human CD4+CD25- Th cells generates so-called induced Treg (iTreg) cells, this phenotype is rapidly lost [19, 21, 22]. Altogether, these observations suggest that more than FOXP3 is necessary for fully explaining the regulatory phenotype.

A plausible explanation for the qualitative and quantitative differences in the expression of FOXP3 in human Th and Treg cells, with their mutually exclusive effector and regulatory functions, is the presence of a Treg-specific higher-order regulatory network [13, 14, 23]. The possibility that Treg-specific control mechanisms can maintain sustained high levels of FOXP3 and can control the regulatory function has been addressed only recently with the identification of the glycoprotein-A repetitions predominant (GARP or LRRC32) receptor [21, 2428].

Identification and characterization of GARP as a safeguard of FOXP3

GARP was identified based on the analysis of gene expression profiling of Treg and Th cells following TCR stimulation, since TCR stimulation does lead to the induction of their mutually exclusive functions [21, 24]. GARP is specifically induced in CD4+CD25hiFOXP3hi Treg cells and thus is a Treg-specific activation marker [21, 2427]. Because the expression of GARP is up-regulated in FOXP3-transduced Th cells, GARP obviously depends on FOXP3, and this finding suggests a potential contribution to the regulatory phenotype [21, 29].

The function of GARP has been elucidated by ectopic over-expression in human alloantigen-specific Th cells and down-regulation of GARP in human antigen-specific Treg cells [21, 29]. Retroviral over-expression of GARP in Th cells, after some rounds of TCR stimulation, leads to an efficient and stable reprogramming/transdifferentiation of the established effector toward the regulatory program. This finding is associated with constitutive expression of FOXP3, the β-galactoside binding protein lectin, galactoside-binding, soluble, 3 (LGALS3) [8, 30], and the cysteine-endoprotease legumain (LGMN) [8] and with an extended Treg-signature with suppression of effector cytokine production and acquisition of regulatory functions similar to those of Treg cells [21, 29]. Thus, a FOXP3-regulating gene has been identified in the human system, and this finding suggests that the GARP signaling pathway may have direct therapeutic applications [28, 31] similar to those that have been described for CD83 in the murine system [32].

In contrast, lentiviral down-regulation of GARP in human alloantigen-specific Treg cells by specific small interfering RNA (siRNA) substantially impairs suppressor function and FOXP3 expression that is associated with impaired induction of CD83 and CD27, both known to regulate FOXP3 [21, 32, 33]. More striking is the fact that similar changes are induced by the down-regulation of FOXP3 in Treg cells, a finding that provides compelling evidence for a GARP-FOXP3 positive feedback loop in Treg cells. Because this feedback loop seems to be interrelated with other FOXP3-regulating systems such as CD83 and CD27, the existence of a higher-order regulatory network as discussed recently by Hori [13], can be speculated (Figure 1a).

Figure 1
figure 1

GARP as safeguard of the regulatory phenotype. (A) Qualitative (lineage-specific) and quantitative (dose-effect) differences in FOXP3 expression in human helper T cells (Th; upper panel) and regulatory T cells (Treg; lower panel) are due to lineage-specific methylation of the respective loci (indicated by black dots) and thus the expression of the genes FOXP3 and GARP. In human Treg cells, a positive feedback loop has been found between GARP and FOXP3; this feedback loop is interrelated with the FOXP3-enhancing molecules indicated. Phosphorylation of LGALS3 (indicated by a P) has been reported to be essential for the FOXP3-regulating function [21]. GARP is a receptor for LAP/latent TGF-β [26, 27]. T-bet (T-box expressed in T cells), GATA3 (GATA-binding protein 3), RORγ (retinoic-related orphan receptor gamma) represent transcription factors of Th1, Th2, and Th17 cells. (B) Implications for human and murine T cells, respectively, of the autocrine and paracrine effects of GARP and Nrp1 surface-bound LAP/latent TGF-β after activation of TGF-β. The TGF-β signature phospho-SMAD2 (pSMAD2) has been observed in human (GARP+) and murine (Nrp1+) Treg cells. Paracrine effects include the generation of infectious tolerance. (C) Structural composition of the LAP/latent TGF-β binding proteins Nrp1 and GARP (LRR, leucine-rich repeat domain; CUB, complement subcomponents C1r/C1s domain; F5/8 coagulation factor domain; MAM, meprin, A5, and receptor protein-tyrosin phosphatase μ domain; TM, transmembrane region; L, leader peptide). NIP (Nrp1 interacting protein) is a Nrp1 binding protein involved in the regulation of Nrp1-mediated signaling as a molecular adapter [48].

Thus, GARP is a specific marker of activated Treg cells and can explain the qualitative and quantitative differences in FOXP3 expression and function in Treg cells and Th cells. Lack of GARP expression further differentiates and explains the transient nature of TGF-β-induced iTreg cells [19], suggesting that natural and iTreg cells may represent alternative differentiation stages of suppressor cells [21, 26]. In line with these observations, a specifically hypomethylated region in intron 1 of GARP and two differentially methylated regions with enhancer functions in Treg cells have recently been characterized. These findings have identified an epigenetic basis for the lineage-specific difference in GARP expression [34].

GARP brings latent TGF-β into a new game

Members of the TGF-β family are pleiotropic cytokines with crucial functions in differentiation, morphogenesis, and immune homeostasis. Their function in immune homeostasis is evidenced by the fact that dysregulation of TGF-β functions is associated with autoimmunity [35]. Like many other cell types, human Treg and Th cells can secrete latent TGF-β [20, 36]. However, latency-associated peptide (LAP) prevents the activation of latent TGF-β toward the active mature TGF-β [37]. The selective induction of LAP and the activation of active TGF-β upon TCR stimulation has been reported only for human Treg cells and clones [20, 37, 38]. This finding further explains the TGF-β specific transcriptional signature and detection of expression of phosphorylated SMAD2 in Treg cells of human and murine origin [20, 23, 37, 39]. Moreover, specific up-regulation of LAP on activated human Treg cells has been shown to allow improvements in the purity of Treg cell isolation procedures by separating activated LAP+FOXP3+ Treg cells from contaminating effector LAP-FOXP3+/lo Th cells [38]. Thus, besides being a marker of activated Treg cells in complex with LAP, TGF-β1 is an important modulator of FOXP3 expression [19, 21, 40], and a potential mediator of infectious tolerance by its action in converting FoxP3- murine CD4+ T cells into functional FoxP3+ iTreg cells [41].

The issue of cell-surface binding of LAP/latent TGF-β on human Treg cells has been addressed only recently with the identification of GARP as a receptor of this complex [26, 27]. Therefore, two important regulatory circuits of Treg cells come together: the GARP-FOXP3 feedback loop and the autocrine TGF-β loop (Figure 1b). With that, the potential synergy of many of the Treg signature components that are essential for the regulatory properties that have been ascribed to TCR activation, interleukin-2, TGF-β, and FOXP3 itself [20, 23] could be explained by this particular spatiotemporal interplay of interrelated signaling systems on Treg cells.

Perspective: does Nrp1 represent a functional homologue of GARP in murine Tregcells?

The identification of GARP as a receptor for LAP/latent TGF-β opens speculation about a potential common denominator. The reason for such speculation is that neuropilin 1 (Nrp1), which has been characterized as a marker of CD4+CD25+ Treg cells in mice that enhances Treg cell/dendritic cell contact during antigen recognition [42, 43], has also been characterized as a receptor for LAP/latent TGF-β [39]. Moreover, murine sorted Nrp1- T cells capture soluble Nrp1 (applied as a constant fragment [Fc]-fusion protein), and the captured Nrp1 increases their ability to bind LAP/TGF-β1. Such coated T cells acquire strong regulatory activity [39]. Thus, Nrp1 is a TGF-β1 receptor that, unlike GARP [27], also activates the latent form of TGF-β1.

The structural differences between GARP, a Toll-like receptor homologue with leucine-rich repeats, and the multi-domain protein Nrp1, a receptor for class-3 semaphorin-family proteins and vascular endothelial growth factor (Figure 1c) [44], necessitate further biochemical and molecular analyses to identify specific binding interactions and potentially associated molecules. The issue of GARP expression in murine Treg cells at the protein level remains to be elucidated.

Discussions

Open Questions Concerning the Function of GARP

Because GARP is constitutively expressed on platelets [26, 45], and because a potential function of GARP on thrombus formation has recently been reported [46], important questions about GARP signaling and parallel function in platelets compared to Treg cells could be considered. Concerning the dependence of GARP expression on FOXP3 as described above, it has been reported that FOXP3 is expressed by human and murine megakaryocytes [47]. Therefore, the thrombocytopenia and platelet abnormalities experienced by some patients with IPEX syndrome can be explained by loss of function of FOXP3 [47]; however, this explanation would suggest a concomitant impairment of GARP expression and function on IPEX platelets, an impairment that has not yet been shown.

A controversial issue is the potential suppressor function of GARP, suggested recently [24], because platelets as a natural source of GARP-expressing cells do not function as suppressor cells [21]. Therefore, differences in the function of GARP in platelets and Treg cells can be suggested. This question is important for the potential design of GARP-selective drugs that can specifically target only Treg cells and not platelet functions. As of now, neither the ligand nor the signaling system or potential co-receptor(s) of GARP has been identified, and identifying them is the most important challenge for the future.

Conclusions

The identification of GARP as a lineage-specific key receptor of human activated Treg cells, which is in part controlled by lineage-specific hypomethylation of the GARP locus, the characterization of a GARP-FOXP3 positive feedback loop that safeguards FOXP3 expression in Treg cells, and the binding of LAP/latent TGF-β to GARP provide a conceptual framework for a new molecular definition of the regulatory program. If GARP is a receptor for the well-known immune modulator TGF-β on human Treg cells, and if Nrp1 plays this same role on murine Treg cells, then this similarity might explain the similarities in the TGF-β signatures that have been observed in Treg cells in both species. The surface binding and activation of TGF-β have obvious implications for infectious tolerance. Complete elucidation of the GARP/GARP-ligand signaling system in Treg cells and platelets is an important challenge and a prerequisite for the future development of strategies and tools for inducing or inhibiting Treg cells in chronic infection, tumor immunotherapy, autoimmune diseases, and transplantation.

Reviewers' comments

Reviewer's report 1

Reviewer 1: Dr. Jim Di Santo, Cytokines and Lymphoid Development Lab, Institut Pasteur, Paris, France

Reviewer's comment: I have read your comment for Biology Direct entitled "FOXP3 and GARP (LRRC32): the master and its minion". I find this comment to be interesting and suitable for publication in Biology Direct. I do not have any specific comments for web publication.

Reviewer's report 2

Reviewer 2: Dr. Benedita Rocha, Institut National de la Santé et de la Recherche Médicale (INSERM) U591, Insitut Necker, France

Reviewer's comment: Regulatory cells have a fundamental role in many disease processes, and extensive experimental and clinical data indicate that tools preventing or increasing regulatory function will have a fundamental therapeutic role. While FOXP3 expression generally correlates with regulation in the mouse, this is not so in human T cells. This comment reviews a fundamental aspect, the factors besides FOXP3 expression that ensure the induction of a stable regulatory function on human cells, their correlation with FOXP3 regulation and their possible mechanisms of action. I found the topic actual and important, the comment clear and comprehensive and strongly support publication.

Reviewer's report 3

Reviewer 3: Dr. Werner Solbach, Insitute for Medical Microbiology and Hygiene, University Lübeck, Germany

Reviewer's comment: The ms. deals with the connectivity of FOXP3 and "glycoprotein - A repititions predominant receptor (GARP or LRRC32) in the context of the functioning of regulatory T cells (Tregs). This topic is of great relevance in the context of clarifying the equivocal role of FOXP3 and its partners for explanation of regulatory T cell circuits. It is clear that not only FOXP3 or GARP alone, but also latently activated TGF-β is crucial for the suppressive activity of Treg cells. The authors now very nicely bring together the GARP - FOXP3 regulatory circuit with the autocrine TGF-β loop which helps to explain many Treg features. In their perspective, they also try to open thoughtful avenues how to bring together (human) GARP with its possible functional homologue in mice, neuropilin 1. In summary, they present a valuable conceptual framework for understanding the regulatory program in the T cell reactivity system and beyond. The ms. is well written and easy to understand. I recommend publication in Biology Direct.

Abbreviations

GARP:

glycoprotein-A repetitions predominant

IPEX:

immune dysregulation, polyendocrinopathy, enteropathy, X-linked

iTreg cells:

induced regulatory T cells

LAP:

latency-associated peptide

Nrp1:

neuropilin 1

SMAD:

Sma- and Mad-related protein 2

TCR:

T-cell receptor

TGF-β:

transforming growth factor-β

Th cells:

helper T cells

Treg cells:

regulatory T cells.

References

  1. Ziegler SF: FOXP3: Of Mice and Men. Annu Rev Immunol. 2006, 24: 209-226. 10.1146/annurev.immunol.24.021605.090547.

    Article  PubMed  CAS  Google Scholar 

  2. Gambineri E, Torgerson TR, Ochs HD: Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatol. 2003, 15: 430-435. 10.1097/00002281-200307000-00010.

    Article  PubMed  CAS  Google Scholar 

  3. Khattri R, Cox T, Yasayko SA, Ramsdell F: An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol. 2003, 4: 337-342. 10.1038/ni909.

    Article  PubMed  CAS  Google Scholar 

  4. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY: Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity. 2005, 22: 329-341. 10.1016/j.immuni.2005.01.016.

    Article  PubMed  CAS  Google Scholar 

  5. Lin W, Haribhai D, Relland L, Truong N, Carlson M, Williams C, Chatila T: Regulatory T cell development in the absence of functional Foxp3. Nat Immunol. 2007, 8: 359-368. 10.1038/ni1445.

    Article  PubMed  CAS  Google Scholar 

  6. Hori S, Nomura T, Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003, 299: 1057-1061. 10.1126/science.1079490.

    Article  PubMed  CAS  Google Scholar 

  7. Fontenot JD, Gavin MA, Rudensky AY: Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003, 4: 330-336. 10.1038/ni904.

    Article  PubMed  CAS  Google Scholar 

  8. Ocklenburg F, Moharregh-Khiabani D, Geffers R, Janke V, Pfoertner S, Garritsen H, Groebe L, Klempnauer J, Dittmar KE, Weiss S, Buer J, Probst-Kepper M: UBD, a downstream element of FOXP3, allows the identification of LGALS3, a new marker of human regulatory T cells. Lab Invest. 2006, 86: 724-737. 10.1038/labinvest.3700432.

    Article  PubMed  CAS  Google Scholar 

  9. Wan YY, Flavell RA: Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. PNAS. 2005, 102: 5126-5131. 10.1073/pnas.0501701102.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Williams LM, Rudensky AY: Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol. 2007, 8: 277-284. 10.1038/ni1437.

    Article  PubMed  CAS  Google Scholar 

  11. Wan YY, Flavell RA: Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature. 2007, 445: 766-770. 10.1038/nature05479.

    Article  PubMed  CAS  Google Scholar 

  12. Allan SE, Passerini L, Bacchetta R, Crellin N, Dai M, Orban PC, Ziegler SF, Roncarolo MG, Levings MK: The role of 2 FOXP3 isoforms in the generation of human CD4 Tregs. J Clin Invest. 2005, 115: 3276-3284. 10.1172/JCI24685.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Hori S: Rethinking the molecular definition of regulatory T cells. Eur J Immunol. 2008, 38: 928-930. 10.1002/eji.200838147.

    Article  PubMed  CAS  Google Scholar 

  14. Roncarolo MG, Gregori S: Is FOXP3 a bona fide marker for human regulatory T cells?. Eur J Immunol. 2008, 38: 925-927. 10.1002/eji.200838168.

    Article  PubMed  CAS  Google Scholar 

  15. Gavin MA, Torgerson TR, Houston E, deRoos P, Ho WY, Stray-Pedersen A, Ocheltree EL, Greenberg PD, Ochs HD, Rudensky AY: Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc Natl Acad Sci USA. 2006, 103: 6659-6664. 10.1073/pnas.0509484103.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Allan SE, Crome SQ, Crellin NK, Passerini L, Steiner TS, Bacchetta R, Roncarolo MG, Levings MK: Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol. 2007, 19: 345-354. 10.1093/intimm/dxm014.

    Article  PubMed  CAS  Google Scholar 

  17. François V, Ottaviani S, Renkvist N, Stockis J, Schuler G, Thielemans K, Colau D, Marchand M, Boon T, Lucas S, Bruggen van der P: The CD4+ T-Cell Response of Melanoma Patients to a MAGE-A3 Peptide Vaccine Involves Potential Regulatory T Cells. Cancer Res. 2009, 69: 4335-4345. 10.1158/0008-5472.CAN-08-3726.

    Article  PubMed  Google Scholar 

  18. Wang F, Ioan-Facsinay A, Voort van der EIH, Huizinga TW, Toes RE: Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol. 2007, 37: 129-138. 10.1002/eji.200636435.

    Article  PubMed  CAS  Google Scholar 

  19. Tran DQ, Ramsey H, Shevach EM: Induction of FOXP3 expression in naive human CD4+FOXP3- T cells by T cell receptor stimulation is TGF{beta}-dependent but does not confer a regulatory phenotype. Blood. 2007, 110: 2983-2990. 10.1182/blood-2007-06-094656.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Stockis J, Fink W, Francois V, Connerotte T, de Smet C, Knoops L, Bruggen van der P, Coulie PG, Lucas S: Comparison of stable human Treg and Th clones by transcriptional profiling. Eur J Immunol. 2009, 39: 869-882. 10.1002/eji.200838807.

    Article  PubMed  CAS  Google Scholar 

  21. Probst-Kepper M, Geffers R, Kröger A, Viegas N, Erck C, Hecht HJ, Lünsdorf H, Roubin R, Moharregh-Khiabani D, Wagner K, Ocklenburg F, Jeron A, Garritsen H, Arstila TP, Kekäläinen E, Balling R, Hauser H, Buer J, Weiss S: GARP: a key receptor controlling FOXP3 in human regulatory T cells. Journal of Cellular and Molecular Medicine. 2010, 13: 3343-3357. 10.1111/j.1582-4934.2009.00782.x.

    Article  Google Scholar 

  22. Takaki H, Ichiyama K, Koga K, Chinen T, Takaesu G, Sugiyama Y, Kato S, Yoshimura A, Kobayashi T: STAT6 Inhibits TGF-β1-mediated Foxp3 Induction through Direct Binding to the Foxp3 Promoter, Which Is Reverted by Retinoic Acid Receptor. J Biol Chem. 2008, 283: 14955-14962. 10.1074/jbc.M801123200.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Hill JA, Feuerer M, Tash K, Haxhinasto S, Perez J, Melamed R, Mathis D, Benoist C: Foxp3 Transcription-Factor-Dependent and -Independent Regulation of the Regulatory T Cell Transcriptional Signature. Immunity. 2007, 27: 786-800. 10.1016/j.immuni.2007.09.010.

    Article  PubMed  CAS  Google Scholar 

  24. Wang R, Wan Q, Kozhaya L, Fujii H, Unutmaz D: Identification of a Regulatory T cell specific Cell Surface Molecule that Mediates Suppressive Signals and Induces Foxp3 Expression. PLoS One. 2008, 3: e27705-

    Google Scholar 

  25. Wang R, Kozhaya L, Mercer F, Khaitan A, Fujii H, Unutmaz D: Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells. PNAS. 2009, 106: 13439-13444.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Tran DQ, Andersson J, Wang R, Ramsey H, Unutmaz D, Shevach EM: GARP (LRRC32) is essential for the surface expression of latent TGF-β on platelets and activated FOXP3+ regulatory T cells. Proc Natl Acad Sci USA. 2009, 106: 13445-13450. 10.1073/pnas.0901944106.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Stockis J, Colau D, Coulie PG, Lucas S: Membrane protein GARP is a receptor for latent TGF-β on the surface of activated human Treg. Eur J Immunol. 2009, 39: 3312-3322.

    Google Scholar 

  28. Probst-Kepper M, Kröger A, Garritsen HSP, Buer J: Perspectives on Regulatory T Cell Therapies. Transfus Med Hemother. 2009, 36: 302-308. 10.1159/000235929.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Probst-Kepper M, Balling R, Buer J: FOXP3: Required but Not Sufficient. The Role of GARP (LRRC32) as a Safeguard of the Regulatory Phenotype. Curr Mol Med. 2010.

    Google Scholar 

  30. Pfoertner S, Jeron A, Probst-Kepper M, Guzman CA, Hansen W, Westendorf AM, Toepfer T, Schrader AJ, Franzke A, Buer J, Geffers R: Signatures of Human Regulatory T Cells: An Encounter with Old Friends and New Players. Genome Biology. 2006, 7: R54-1-R54-18. 10.1186/gb-2006-7-7-r54.

    Article  Google Scholar 

  31. Tran DQ, Shevach EM: Therapeutic potential of FOXP3 regulatory T cells and their interactions with dendritic cells. Hum Immunol. 2009, 70: 294-299. 10.1016/j.humimm.2009.02.007.

    Article  PubMed  CAS  Google Scholar 

  32. Reinwald S, Wiethe C, Westendorf AM, Breloer M, Probst-Kepper M, Fleischer B, Steinkasserer A, Buer J, Hansen W: CD83 Expression in CD4+ T Cells Modulates Inflammation and Autoimmunity. J Immunol. 2008, 180: 5890-5897.

    Article  PubMed  CAS  Google Scholar 

  33. Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM: CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25 T cells. Blood. 2008, 110: 2537-2544. 10.1182/blood-2007-03-082578.

    Article  Google Scholar 

  34. Schmidl C, Klug M, Boeld TJ, Andreesen R, Hoffmann P, Edinger M, Rehli M: Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity. Genome Res. 2009, 19: 1165-1174. 10.1101/gr.091470.109.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Wan YY, Flavell RA: TGF-beta and regulatory T cell in immunity and autoimmunity. J Clin Immunol. 2009, 28: 647-659. 10.1007/s10875-008-9251-y.

    Article  Google Scholar 

  36. Levings MK, Sangregorio R, Sartirana C, Moschin AL, Battaglia M, Orban PC, Roncarolo MG: Human CD25+CD4+ T suppressor cell clones produce transforming growth factor beta, but not interleukin 10, and are distinct from type 1 T regulatory cells. J Exp Med. 2002, 196: 1335-1346. 10.1084/jem.20021139.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Nakamura K, Kitani A, Fuss I, Pedersen A, Harada N, Nawata H, Strober W: TGF-beta1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol. 2004, 172: 834-842.

    Article  PubMed  CAS  Google Scholar 

  38. Tran DQ, Andersson J, Hardwick D, Bebris L, Illei GG, Shevach EM: Selective expression of latency-associated peptide (LAP) and IL-1 receptor type I/II (CD121a/CD121b) on activated human FOXP3+ regulatory T cells allows for their purification from expansion cultures. Blood. 2009, 113: 5125-5133. 10.1182/blood-2009-01-199950.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Glinka J, Prud'homme GJ: Neuropilin-1 is a receptor for transforming growth factor -1, activates its latent form, and promotes regulatory T cell activity. J Leukoc Biol. 2008, 84: 302-310. 10.1189/jlb.0208090.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF: Cutting Edge: TGF-beta Induces a Regulatory Phenotype in CD4+CD25- T Cells through Foxp3 Induction and Down-Regulation of Smad7. J Immunol. 2004, 172: 5149-5153.

    Article  PubMed  CAS  Google Scholar 

  41. Andersson J, Tran DQ, Pesu M, Davidson TS, Ramsey H, O'Shea JJ, Shevach EM: CD4 FoxP3 regulatory T cells confer infectious tolerance in a TGF-beta-dependent manner. J Exp Med. 2008, 205: 1975-1981. 10.1084/jem.20080308.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. Bruder D, Probst-Kepper M, Westendorf AM, Geffers R, Beissert S, Loser K, von Boehmer H, Buer J, Hansen W: Frontline: Neuropilin-1: a surface marker of regulatory T cells. Eur J Immunol. 2004, 34: 623-630. 10.1002/eji.200324799.

    Article  PubMed  CAS  Google Scholar 

  43. Sarris M, Andersen KG, Randow F, Mayr L, Betz AG: Neuropilin-1 Expression on Regulatory T Cells Enhances Their Interaction with Dendritic Cells during Antigen Recognition. Immunity. 2008, 28: 402-413. 10.1016/j.immuni.2008.01.012.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. Geretti E, Klagsbrun M: Neuropilins: Novel Targets for Anti-Angiogenesis Therapies. Cell Adh Migr. 2007, 1: 56-61. 10.4161/cam.1.2.4490.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Macaulay IC, Tijssen MR, Thijssen-Timmer DC, Gusnanto A, Steward M, Burns P, Langford CF, Ellis P, Dudbridge F, Zwaginga JJ, Watkins NA, Schoot van der CE, Ouwehand WH: Comparative gene expression profiling of in vitro differentiated megakaryocytes and erythroblasts identifies novel activatory and inhibitory platelet membrane proteins. Blood. 2007, 109: 3260-3269. 10.1182/blood-2006-07-036269.

    Article  PubMed  CAS  Google Scholar 

  46. O'Connor N, Salles I, Cvejic A, Watkins NA, Walker A, Garner S, Macaulay IC, Steward M, Zwaginga J, Bray S, Dudbridge F, de Bono B, Goodall AH, Deckmyn H, Stemple DL, Ouwehand WH, Bloodomics Consortium: Functional genomics in zebrafish permits rapid characterization of novel platelet membrane proteins. Blood. 2008, 113: 4754-4762. 10.1182/blood-2008-06-162693.

    Article  PubMed  Google Scholar 

  47. Bernard JJ, Seweryniak KE, Koniski AD, Spinelli SL, Blumberg N, Francis CW, Taubman MB, Palis J, Phipps RP: Foxp3 Regulates Megakaryopoiesis and Platelet Function. Arterioscler Thromb Vasc Biol. 2009, 29: 1874-1882. 10.1161/ATVBAHA.109.193805.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  48. Cai H, Reed RR: Cloning and Characterization of Neuropilin-1-Interacting Protein: A PSD-95/Dlg/ZO-1 Domain-Containing Protein That Interacts with the Cytoplasmic Domain of Neuropilin-1. J Neurosci. 1999, 19: 6519-6527.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Michael Probst-Kepper was supported by grants from the VolkswagenStiftung (I/73 234) and the Deutsche Forschungsgemeinschaft (PR554/2).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael Probst-Kepper.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

MPK and JB both were involved in drafting of the manuscript and approved the final version to be published.

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article

Probst-Kepper, M., Buer, J. FOXP3 and GARP (LRRC32): the master and its minion. Biol Direct 5, 8 (2010). https://doi.org/10.1186/1745-6150-5-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/1745-6150-5-8

Keywords