- Email: [email protected]
Regulatory T cells: From bench to bedside
International Immunopharmacology 9 (2009) 515–517
Contents lists available at ScienceDirect
International Immunopharmacology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i n t i m p
Editorial
Regulatory T cells: From bench to bedside Shuiping Jiang Shantou University Medical College, Shantou, China Department of Nephrology and Transplantation, King's College London, Guy’s Hospital, London SE1 9RT, United Kingdom
a r t i c l e
i n f o
Article history: Accepted 28 January 2008 Keywords: Regulatory T cells Tregs Foxp3 China Tregs 2008 Th17 Transplantation tolerance Autoimmune disease Cancer Adoptive cell therapy
a b s t r a c t Regulatory T cells (Tregs) are subsets of T cells that are specifically dedicated to controlling immune responses. It has been established that Tregs play a key role in regulating autoimmune disease, allergy, cancer, infectious disease, and in the induction of transplantation tolerance. The latest progress in the development, function, mechanism of action, and homeostasis of regulatory T cells, and their translation to the clinic were presented at the International Conference on Regulatory T Cells and Clinical Application in Human Diseases in Beijing on 25–27 October 2008 (China Tregs 2008). In this Special Issue of International Immunopharmacology, several papers submitted to the China Tregs 2008 will highlight some of the recent advances in the biology of regulatory T cells and current strategies to translate regulatory T cells into the clinic. © 2009 Elsevier B.V. All rights reserved.
1. Introduction In the past decade several subsets of regulatory T cells (Tregs) have been described in both human and rodents [1]. Among them are naturally occurring CD4+CD25+ Tregs. The importance of this population of Tregs in the control of autoimmunity was first demonstrated by Sakaguchi et al. in 1995 [2]. They showed that the spontaneous development of autoimmune disease in thymectomised neonate mice could be prevented by the adoptive transfer of CD4+CD25+ T cells from normal mice [2]. Subsequent studies have showed that transcript factor Foxp3 gene appears to play a key role in the ontogeny of CD4+CD25+ Tregs [3,4]. Mutation of Foxp3 gene in human causes the IPEX syndrome [5]. Now it is clear that Tregs are the key regulators for the control of all immune responses including autoimmunity, tumor immunity, infection, allergic reaction and transplantation tolerance, and their translation to the clinic would lead to cure many forms of human diseases [1]. In October 2008, an international conference held in Beijing, China (China Tregs 2008) was dedicated entirely to the latest progress in the biology of Tregs including their development, function, mechanism of action, and homeostasis, and their clinical application in human diseases [6]. 2. Foxp3 biochemistry and the development, homeostasis, stability and function of Tregs Foxp3 is key regulator for Treg function and homeostasis. In this Special Issue of China Tregs 2008, Zhou et al. from University of
E-mail address: [email protected]. 1567-5769/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.intimp.2008.01.038
Pennsylvania (USA) summarized their recent data on the structure and the ensemble of Foxp3 transcription factor. The crystal structure of Foxp3 revealed that Foxp3 oligomerization domain as an antiparallel coiled coil with a potential to mediate high-order homo or hetero oligomerization. The homo-oligomerization of Foxp3 would promote proper organization of the forkhead domain for efficient DNA binding, thus affecting Treg stability. Foxp3 forms complex with several proteins including histone H1 and chromatin remodeling factors. The chromatin remodeling BAF complex regulates gene expression through the activity of Brg (Brahma-related gene). In this issue, Jani et al. from Yale University (USA) showed that in Brg conditional KO mice, in which Brg was deleted at the double positive (DP) stage in the thymus, the Treg population was specifically affected. These mice displayed lympho-proliferative syndrome 2–4 months of age with enlarged peripheral lymphoid organs and leukocyte infiltration in non-lymphoid organs, illustrating the specific role of the Brgcontaining BAF complex in controlling Treg functions. Posttranscriptional modification of Foxp3 by inhibitory microRNA (miRNA) is also important for Treg function. Recent studies have showed that Dicer-deficient Tregs were less suppressive, less proliferative and more prone to apoptosis under noninflammatory conditions than were wild-type (WT) Tregs [7]. When doublefluorescent knock-in mice were used, Dicer-deficient Tregs may lose Foxp3 protein and become pathogenic memory cells or effector cells [8]. In this issue, Zhou et al. from Henry Ford Hospital (Michigan, USA) provided an overview of the important role of miRNAs in the development, stability and function of Tregs. Tregs express different Toll-like receptor (TLRs), and Treg function can be attenuated or augmented depending on the nature of TLR
516
S. Jiang / International Immunopharmacology 9 (2009) 515–517
stimulation. In this issue, Dai et al. from University of Connecticut (USA) described the recent links between Treg biology and TLRs. Endogenous inflammatory stimuli would also play a role in the mechanism of Tregmediated suppression. Lee et al. from University of Toronto (Canada) provided elegant evidence that E prostanoid receptor 2 (EP2), a receptor for prostaglandin E2 (PGE2), was expressed by regulatory αβTCR+ CD4− CD8− NK1.1− double negative T (DN Treg) cell clones but not by their non-regulatory natural mutants. They further showed that PGE2 signaling through E prostanoid receptor 2 impaired the proliferative response of DN Tregs. 3. Treg therapy in autoimmunity, cancer, and transplantation tolerance Naïve CD4+ T cells are able to differentiate into either Tregs (induced Tregs: iTregs) or IL-17 producing effector Th17 cells under immunosuppressive milieu of TGF-b or inflammatory condition of TGF-b and IL-6. In this Special Issue of China Tregs 2008, Huter et al. from National Institutes of Health (NIH, USA) demonstrated that antigen-specific iTregs were more potent than polyclonal iTregs in inhibiting Th17-mediated autoimmune gastritis, and polyclonal nTreg had no effect. Their data are in line with our recent findings that alloantigen-specific Tregs were more potent suppressors than polyclonal Tregs for the induction of transplantation tolerance [9–11]. In vitro-expanded alloantigen-specific Tregs are promising reagents for promoting clinical transplantation tolerance [1]. Several papers in this issue have provided further evidence to support this notion. Lu et al. from Nanjing (China) showed that in vitro-expanded Tregs contributed not only to liver transplantation tolerance, but also were able to attenuate hepatic ischemia-reperfusion injury. Low-dose of immunosuppressive drug Sirolimus preserved Tregs function in mice as showed by Ma et al. from the University of Montréal (Canada), and low-dose of Tacrolimus favored the induction of Tregs in transplant patients as reported by Wang et al. from Beijing (China). Hall et al. from the University of New South Wales (Australia) showed that Th1 and Th2 responses promoted the development of two different pathways of alloantigen specific Tregs in vivo, depending on the cytokine melieu. In addition to the in vitro-expanded Tregs as a potential therapeutical tool, and the induction of Tregs in vivo by pharmacological agents would represent a very attractive approach to promote specific immunosuppression. In this issue, Xie et al. from Osaka University (Japan) showed that Curcumin, a naturally occurring polyphenolic phytochemical isolated from the rhizome of the medicinal plant curcuma longa, significantly reduced experimental autoimmune encephalomyelitis (EAE) through inhibition of IL-17 production by effector Th17 cells. On the other hand, Shi et al. from Beijing (China) reported that Cordyceps Sinensis, a traditional Chinese medicine from a parasitic fungus, was able to increase the regulatory T cells to Th17 cell ratio in vivo and delayed the onset of diabetes in NOD mice. UV-irradiation has long been associated with the development of skin cancer. Interestingly, Loser et al. from University of Münster (Germany) showed that UV-irradiation was able to expand Tregs by epidermal Langerhans cells through the vitamin D3 or RANK-RANKL (CD254) signaling pathway, thus strengthening the notion that UV irradiation leads to the inhibition T cell mediated cutaneous immunity and facilitate the development of skin cancer. Many studies have showed that in cancer patients Tregs have an played important role in inhibiting host immunity against cancer. Current strategies are aimed to target Tregs in vivo. In this issue, Li et al. from Guangzhou (China) summarized their recent findings on EBV-specific Tregs in EBV associated cancer patients, and they proposed several possible interventions of targeting Tregs in the immunotherapy against EBV-positive cancers. On the other hand, Zhang et al. from Shanghai (China) showed that immunization of
irradiated mitogen-activated autologous T cells significantly enhanced anti-tumor immunity in vivo, and this was due to reduced Treg functions and the inhibition of activation-induced cell death in effector T cells, implying that autologous T cell immunization would be a potential new strategy for cancer immune therapy. Embryonic stem cells (ESC) are potential in repairing damaged organs and tissues. Mesenchymal stem cells (MSC) possess immunoregulatory functions in various animal models. In collagen-induced arthritis, a mouse model for human rheumatoid arthritis, Tasso et al. from University of Genova (Italy) reported that infusion of MSC not only inhibited the disease, but also induced the generation of antigenspecific Tregs, providing an interesting interplay between MSC and Tregs in controlling autoimmune disease. 4. Preclinical studies of Tregs in primates and in patients It has been showed that CD4+CD25+ Tregs have impaired suppressive function in multiple sclerosis (MS) patients [12]. In this issue, Ma et al. from University of Montréal (Canada) studied the number and function of Tregs in a mimic model of human MS in Cynomolgus Monkeys. They found that dysfunction of CD4+CD25+ Tregs and IL-10 producing type 1 regulatory T cells (Tr1 cells) contributed to the pathogenesis of the disease, and adoptive transfer of Tregs would be a clinical applicable strategy to treat MS. Tregs represent about 10% CD4+ T cells in the periphery blood of humans. Adoptive Treg therapy in humans would require large number of Tregs [1]. In this issue, Brun et al. from TxCell (France) presented the expansion of clinical grade Tr1 cells under GMP conditions for severe Crohn's disease in patients. Tregs generated from the PBMCs of Crohn's disease patients were able to expand up to 1 billion cells. A phase I/IIa clinical trial to test the efficacy of expanded Tregs in severe refractory Crohn's disease patients is underway. 5. Conclusion At China Tregs 2008, more than 60 of world's most renowned Treg experts gave the sought-after plenary presentations on the biology of Tregs and its clinical application in human diseases. Further 40 plenary oral presentations and 200 abstracts were also presented at the conference. The presentations of world's most senior speakers have been featured in the recently published textbook “Regulatory T cells and Clinical Application” (Springer, New York), edited by Shuiping Jiang [1], and in the Meeting Report published in Science Signaling [6]. It is clear from the China Tregs 2008 that the immunobiology of Tregs is being unraveled, and new therapeutical opportunities are emerging for immune intervention using Tregs in autoimmune disease, allergy, cancer, infectious disease, and in the induction of clinical transplantation tolerance. The preclinical studies of Tregs in various forms of human diseases are well advanced, and the results of many current clinical trials of Tregs would be presented in the future China Tregs meetings, and will shed light on the efficacy of Treg therapy. References [1] Jiang S, editor. Regulatory T Cells and Clinical Application. New York: Springer; 2008. [2] Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing Il-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155(3):1151–64. [3] Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299(5609):1057–61. [4] Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4(4):330–6. [5] Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001;27(1):20–1.
S. Jiang / International Immunopharmacology 9 (2009) 515–517 [6] Game DS, Cao X, Jiang S. Regulatory T cells: the cunning fox and its clinical application. Sci Signal Dec 23 2008;1(51) mr3. [7] Liston A, Lu LF, O'Carroll D, Tarakhovsky A, Rudensky AY. Dicer-dependent microRNA pathway safeguards regulatory T cell function. J Exp Med Sep 1 2008;205(9):1993–2004. [8] Zhou X, Jeker LT, Fife BT, Zhu S, Anderson MS, McManus MT, et al. Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity. J Exp Med Sep 1 2008;205(9):1983–91. [9] Jiang S, Tsang J, Game DS, Stevenson S, Lombardi G, Lechler RI. Generation and expansion of human CD4+ CD25+ regulatory T cells with indirect allospecificity:
517
potential reagents to promote donor-specific transplantation tolerance. Transplantation Dec 27 2006;82(12):1738–43. [10] Golshayan D, Jiang S, Tsang J, Garin MI, Mottet C, Lechler RI. In vitro-expanded donor alloantigen-specific CD4+CD25+ regulatory T cells promote experimental transplantation tolerance. Blood Jan 15 2007;109(2):827–35. [11] Jiang S, Camara N, Lombardi G, Lechler RI. Induction of allopeptide-specific human CD4+CD25+ regulatory T cells ex vivo. Blood Sep 15 2003;102(6):2180–6. [12] Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 2004;199(7):971–9.
Contents lists available at ScienceDirect
International Immunopharmacology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i n t i m p
Editorial
Regulatory T cells: From bench to bedside Shuiping Jiang Shantou University Medical College, Shantou, China Department of Nephrology and Transplantation, King's College London, Guy’s Hospital, London SE1 9RT, United Kingdom
a r t i c l e
i n f o
Article history: Accepted 28 January 2008 Keywords: Regulatory T cells Tregs Foxp3 China Tregs 2008 Th17 Transplantation tolerance Autoimmune disease Cancer Adoptive cell therapy
a b s t r a c t Regulatory T cells (Tregs) are subsets of T cells that are specifically dedicated to controlling immune responses. It has been established that Tregs play a key role in regulating autoimmune disease, allergy, cancer, infectious disease, and in the induction of transplantation tolerance. The latest progress in the development, function, mechanism of action, and homeostasis of regulatory T cells, and their translation to the clinic were presented at the International Conference on Regulatory T Cells and Clinical Application in Human Diseases in Beijing on 25–27 October 2008 (China Tregs 2008). In this Special Issue of International Immunopharmacology, several papers submitted to the China Tregs 2008 will highlight some of the recent advances in the biology of regulatory T cells and current strategies to translate regulatory T cells into the clinic. © 2009 Elsevier B.V. All rights reserved.
1. Introduction In the past decade several subsets of regulatory T cells (Tregs) have been described in both human and rodents [1]. Among them are naturally occurring CD4+CD25+ Tregs. The importance of this population of Tregs in the control of autoimmunity was first demonstrated by Sakaguchi et al. in 1995 [2]. They showed that the spontaneous development of autoimmune disease in thymectomised neonate mice could be prevented by the adoptive transfer of CD4+CD25+ T cells from normal mice [2]. Subsequent studies have showed that transcript factor Foxp3 gene appears to play a key role in the ontogeny of CD4+CD25+ Tregs [3,4]. Mutation of Foxp3 gene in human causes the IPEX syndrome [5]. Now it is clear that Tregs are the key regulators for the control of all immune responses including autoimmunity, tumor immunity, infection, allergic reaction and transplantation tolerance, and their translation to the clinic would lead to cure many forms of human diseases [1]. In October 2008, an international conference held in Beijing, China (China Tregs 2008) was dedicated entirely to the latest progress in the biology of Tregs including their development, function, mechanism of action, and homeostasis, and their clinical application in human diseases [6]. 2. Foxp3 biochemistry and the development, homeostasis, stability and function of Tregs Foxp3 is key regulator for Treg function and homeostasis. In this Special Issue of China Tregs 2008, Zhou et al. from University of
E-mail address: [email protected]. 1567-5769/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.intimp.2008.01.038
Pennsylvania (USA) summarized their recent data on the structure and the ensemble of Foxp3 transcription factor. The crystal structure of Foxp3 revealed that Foxp3 oligomerization domain as an antiparallel coiled coil with a potential to mediate high-order homo or hetero oligomerization. The homo-oligomerization of Foxp3 would promote proper organization of the forkhead domain for efficient DNA binding, thus affecting Treg stability. Foxp3 forms complex with several proteins including histone H1 and chromatin remodeling factors. The chromatin remodeling BAF complex regulates gene expression through the activity of Brg (Brahma-related gene). In this issue, Jani et al. from Yale University (USA) showed that in Brg conditional KO mice, in which Brg was deleted at the double positive (DP) stage in the thymus, the Treg population was specifically affected. These mice displayed lympho-proliferative syndrome 2–4 months of age with enlarged peripheral lymphoid organs and leukocyte infiltration in non-lymphoid organs, illustrating the specific role of the Brgcontaining BAF complex in controlling Treg functions. Posttranscriptional modification of Foxp3 by inhibitory microRNA (miRNA) is also important for Treg function. Recent studies have showed that Dicer-deficient Tregs were less suppressive, less proliferative and more prone to apoptosis under noninflammatory conditions than were wild-type (WT) Tregs [7]. When doublefluorescent knock-in mice were used, Dicer-deficient Tregs may lose Foxp3 protein and become pathogenic memory cells or effector cells [8]. In this issue, Zhou et al. from Henry Ford Hospital (Michigan, USA) provided an overview of the important role of miRNAs in the development, stability and function of Tregs. Tregs express different Toll-like receptor (TLRs), and Treg function can be attenuated or augmented depending on the nature of TLR
516
S. Jiang / International Immunopharmacology 9 (2009) 515–517
stimulation. In this issue, Dai et al. from University of Connecticut (USA) described the recent links between Treg biology and TLRs. Endogenous inflammatory stimuli would also play a role in the mechanism of Tregmediated suppression. Lee et al. from University of Toronto (Canada) provided elegant evidence that E prostanoid receptor 2 (EP2), a receptor for prostaglandin E2 (PGE2), was expressed by regulatory αβTCR+ CD4− CD8− NK1.1− double negative T (DN Treg) cell clones but not by their non-regulatory natural mutants. They further showed that PGE2 signaling through E prostanoid receptor 2 impaired the proliferative response of DN Tregs. 3. Treg therapy in autoimmunity, cancer, and transplantation tolerance Naïve CD4+ T cells are able to differentiate into either Tregs (induced Tregs: iTregs) or IL-17 producing effector Th17 cells under immunosuppressive milieu of TGF-b or inflammatory condition of TGF-b and IL-6. In this Special Issue of China Tregs 2008, Huter et al. from National Institutes of Health (NIH, USA) demonstrated that antigen-specific iTregs were more potent than polyclonal iTregs in inhibiting Th17-mediated autoimmune gastritis, and polyclonal nTreg had no effect. Their data are in line with our recent findings that alloantigen-specific Tregs were more potent suppressors than polyclonal Tregs for the induction of transplantation tolerance [9–11]. In vitro-expanded alloantigen-specific Tregs are promising reagents for promoting clinical transplantation tolerance [1]. Several papers in this issue have provided further evidence to support this notion. Lu et al. from Nanjing (China) showed that in vitro-expanded Tregs contributed not only to liver transplantation tolerance, but also were able to attenuate hepatic ischemia-reperfusion injury. Low-dose of immunosuppressive drug Sirolimus preserved Tregs function in mice as showed by Ma et al. from the University of Montréal (Canada), and low-dose of Tacrolimus favored the induction of Tregs in transplant patients as reported by Wang et al. from Beijing (China). Hall et al. from the University of New South Wales (Australia) showed that Th1 and Th2 responses promoted the development of two different pathways of alloantigen specific Tregs in vivo, depending on the cytokine melieu. In addition to the in vitro-expanded Tregs as a potential therapeutical tool, and the induction of Tregs in vivo by pharmacological agents would represent a very attractive approach to promote specific immunosuppression. In this issue, Xie et al. from Osaka University (Japan) showed that Curcumin, a naturally occurring polyphenolic phytochemical isolated from the rhizome of the medicinal plant curcuma longa, significantly reduced experimental autoimmune encephalomyelitis (EAE) through inhibition of IL-17 production by effector Th17 cells. On the other hand, Shi et al. from Beijing (China) reported that Cordyceps Sinensis, a traditional Chinese medicine from a parasitic fungus, was able to increase the regulatory T cells to Th17 cell ratio in vivo and delayed the onset of diabetes in NOD mice. UV-irradiation has long been associated with the development of skin cancer. Interestingly, Loser et al. from University of Münster (Germany) showed that UV-irradiation was able to expand Tregs by epidermal Langerhans cells through the vitamin D3 or RANK-RANKL (CD254) signaling pathway, thus strengthening the notion that UV irradiation leads to the inhibition T cell mediated cutaneous immunity and facilitate the development of skin cancer. Many studies have showed that in cancer patients Tregs have an played important role in inhibiting host immunity against cancer. Current strategies are aimed to target Tregs in vivo. In this issue, Li et al. from Guangzhou (China) summarized their recent findings on EBV-specific Tregs in EBV associated cancer patients, and they proposed several possible interventions of targeting Tregs in the immunotherapy against EBV-positive cancers. On the other hand, Zhang et al. from Shanghai (China) showed that immunization of
irradiated mitogen-activated autologous T cells significantly enhanced anti-tumor immunity in vivo, and this was due to reduced Treg functions and the inhibition of activation-induced cell death in effector T cells, implying that autologous T cell immunization would be a potential new strategy for cancer immune therapy. Embryonic stem cells (ESC) are potential in repairing damaged organs and tissues. Mesenchymal stem cells (MSC) possess immunoregulatory functions in various animal models. In collagen-induced arthritis, a mouse model for human rheumatoid arthritis, Tasso et al. from University of Genova (Italy) reported that infusion of MSC not only inhibited the disease, but also induced the generation of antigenspecific Tregs, providing an interesting interplay between MSC and Tregs in controlling autoimmune disease. 4. Preclinical studies of Tregs in primates and in patients It has been showed that CD4+CD25+ Tregs have impaired suppressive function in multiple sclerosis (MS) patients [12]. In this issue, Ma et al. from University of Montréal (Canada) studied the number and function of Tregs in a mimic model of human MS in Cynomolgus Monkeys. They found that dysfunction of CD4+CD25+ Tregs and IL-10 producing type 1 regulatory T cells (Tr1 cells) contributed to the pathogenesis of the disease, and adoptive transfer of Tregs would be a clinical applicable strategy to treat MS. Tregs represent about 10% CD4+ T cells in the periphery blood of humans. Adoptive Treg therapy in humans would require large number of Tregs [1]. In this issue, Brun et al. from TxCell (France) presented the expansion of clinical grade Tr1 cells under GMP conditions for severe Crohn's disease in patients. Tregs generated from the PBMCs of Crohn's disease patients were able to expand up to 1 billion cells. A phase I/IIa clinical trial to test the efficacy of expanded Tregs in severe refractory Crohn's disease patients is underway. 5. Conclusion At China Tregs 2008, more than 60 of world's most renowned Treg experts gave the sought-after plenary presentations on the biology of Tregs and its clinical application in human diseases. Further 40 plenary oral presentations and 200 abstracts were also presented at the conference. The presentations of world's most senior speakers have been featured in the recently published textbook “Regulatory T cells and Clinical Application” (Springer, New York), edited by Shuiping Jiang [1], and in the Meeting Report published in Science Signaling [6]. It is clear from the China Tregs 2008 that the immunobiology of Tregs is being unraveled, and new therapeutical opportunities are emerging for immune intervention using Tregs in autoimmune disease, allergy, cancer, infectious disease, and in the induction of clinical transplantation tolerance. The preclinical studies of Tregs in various forms of human diseases are well advanced, and the results of many current clinical trials of Tregs would be presented in the future China Tregs meetings, and will shed light on the efficacy of Treg therapy. References [1] Jiang S, editor. Regulatory T Cells and Clinical Application. New York: Springer; 2008. [2] Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing Il-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155(3):1151–64. [3] Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299(5609):1057–61. [4] Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4(4):330–6. [5] Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001;27(1):20–1.
S. Jiang / International Immunopharmacology 9 (2009) 515–517 [6] Game DS, Cao X, Jiang S. Regulatory T cells: the cunning fox and its clinical application. Sci Signal Dec 23 2008;1(51) mr3. [7] Liston A, Lu LF, O'Carroll D, Tarakhovsky A, Rudensky AY. Dicer-dependent microRNA pathway safeguards regulatory T cell function. J Exp Med Sep 1 2008;205(9):1993–2004. [8] Zhou X, Jeker LT, Fife BT, Zhu S, Anderson MS, McManus MT, et al. Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity. J Exp Med Sep 1 2008;205(9):1983–91. [9] Jiang S, Tsang J, Game DS, Stevenson S, Lombardi G, Lechler RI. Generation and expansion of human CD4+ CD25+ regulatory T cells with indirect allospecificity:
517
potential reagents to promote donor-specific transplantation tolerance. Transplantation Dec 27 2006;82(12):1738–43. [10] Golshayan D, Jiang S, Tsang J, Garin MI, Mottet C, Lechler RI. In vitro-expanded donor alloantigen-specific CD4+CD25+ regulatory T cells promote experimental transplantation tolerance. Blood Jan 15 2007;109(2):827–35. [11] Jiang S, Camara N, Lombardi G, Lechler RI. Induction of allopeptide-specific human CD4+CD25+ regulatory T cells ex vivo. Blood Sep 15 2003;102(6):2180–6. [12] Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 2004;199(7):971–9.