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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/08/22 08:01:28」(JST)

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制御性T細胞（せいぎょせいTさいぼう、英: regulatory T cell, Treg、調節性T細胞とも）は、免疫応答の抑制的制御（免疫寛容）を司るT細胞の一種。免疫応答機構の過剰な免疫応答を抑制するためのブレーキ（負の制御機構）や、免疫の恒常性維持で重要な役割を果たす。制御性T細胞の発生には、Foxp3誘導のほか、それとは別系統のTCR刺激によるDNAの配列変化を伴わない遺伝子機能の変化（エピジェネティクス参照）により、T細胞が制御性T細胞に分化すると考えられる^[1]。

概要

1971年リチャード・ガーションらはT細胞の移入により免疫寛容を引き起こすことができることを明らかにし、このT細胞サブセットを｢抑制性T細胞｣と名づけた^[2]。この時点において｢抑制性T細胞｣とは単なる概念に過ぎず、存在の確認はされていなかった。1995年には京都大学の坂口志文らによってインターロイキン-2受容体α鎖であるCD25分子を発現するT細胞が自己免疫疾患を抑制する機能を有することが明らかにされた^[3]。このCD4⁺CD25⁺T細胞は抑制性T細胞の中でも区別して｢CD4⁺CD25⁺Treg｣と呼ばれるようになった。はじめはCD4およびCD25をCD4⁺CD25⁺Tregのマーカーとして用いていたが、いずれもこの細胞に特異的なものではなくマーカーとして用いるには問題があった。その後転写因子であるFoxp3がCD4⁺CD25⁺Tregにおける特異的分子マーカーであると共にTreg分化のマスター遺伝子であることが明らかになるなど急速に研究が進展した。近年ではCD4⁺CD25⁺Tregの他にもいくつかのサブセットがあることが分かっている。Tregは内在性T細胞（英: Naturally Occurring Regulatory T cell, nTreg）と、ナイーブCD4陽性T細胞から分化させる自己認識能の低い誘導性T細胞（英: Inducible Regulatory T cell, iTreg）に大きく二つに分類される。内在性Tregは胸腺内において自己反応性T細胞と共に産生される。一方、誘導性TregはTGF-βの存在下における抗原刺激により末梢血中のナイーブT細胞から分化誘導され、いずれも免疫寛容の機構に関与している。両者の最大の差異は、T細胞受容体の抗原特異性と、Foxp3発現の安定性であり、Foxp3発現が誘導性T細胞で不安定なのは遺伝子のエピジェネティックな制御の違いによるのではないかと推察されている^[4]。

分類・機能

免疫系の機能は自己と非自己を区別して非自己を排除することであり、免疫系の過剰な働きによって生じる自己反応性によって自己免疫疾患に陥る。制御性T細胞は免疫系の崩壊を抑制し、免疫異常から生体を守っている。また、Tregは自己免疫のみでなく炎症や腫瘍免疫、感染免疫などについても抑制作用を示すことが明らかになっている。制御性T細胞が免疫抑制作用を発現するメカニズムは未だ十分に明らかになってはいないが、細胞同士の直接的な相互作用あるいは抑制的サイトカインであるTGF-βおよびIL-10の放出によると考えられている。Tregのサブセットの代表的なものとしては以下のようなものが知られている。

内在性Treg

Foxp3⁺CD25⁺Treg
NKT細胞（Natural Killer T細胞）
CD8⁺CD122⁺Treg

誘導性Treg

Foxp3⁺Treg
タイプI Treg（Tr1）
Qa-1a拘束性CD8⁺Treg

発生・分化機構

胸腺で分化した新生T細胞は未熟な状態であり、CD4抗原もCD8抗原もなければ（ダブルネガティブ、DN）T細胞受容体（TCR）も有していない。DN細胞はCD8⁺シングルポジティブ（SP）細胞を経てCD4⁺CD8⁺T細胞（ダブルポジティブ（DP）細胞）へと分化していく。これらの過程中においてTCR遺伝子の再編成が行われ、TCRの多様性の形成が行われていくが、中には自己抗原に対して反応性を示すものも産生され自己免疫疾患に陥る可能性がある。そのためこれらのクローンを除去するためにポジティブセレクションおよびネガティブセレクションと呼ばれる、いわば適切なT細胞のみを分化させるためにふるいにかけるようなことが行われる。ポジティブセレクションは胸腺の皮質で行われ、CD4⁺CD8⁺T細胞の中から外来性抗原に対して反応性を持つTCRを有するものを選別する機構である。一方、ネガティブセレクションとは自己抗原に対して反応性を持つ細胞を選別する反応であり、ネガティブセレクションを受けた細胞はアポトーシス（自発的細胞死）に導かれこの段階で通常脱落していく。制御性T細胞もそのほかのT細胞と同様に独立した系列として胸腺内で分化していくと考えられている。

未成熟T細胞は胸腺上皮細胞による自己抗原の提示を受けてFoxp3を発現し、CD4⁺CD25⁺Tregへと分化が誘導されることが知られている。Foxp3はIPEX（Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked）症候群患者およびscurfyマウスにおける自己免疫疾患の原因遺伝子として同定された^[5]。Foxp3はFoxp3⁺CD25⁺Tregへの分化およびその機能に関与する遺伝子である。一方、末梢においてもTGF-βの刺激を受けることによってFoxp3の発現が誘導されることが報告されており、IL-6とTGF-βの共刺激によってTh17細胞への分化が促進されてしまうためにTregへの分化は抑制される。

出典

『実験医学 2007年11月号』羊土社 ISBN 978-4-7581-0029-8

参考文献

^ Naganari Ohkura, Masahide Hamaguchi et al.「T Cell Receptor Stimulation-Induced Epigenetic Changes and Foxp3 Expression Are Independent and Complementary Events Required for Treg Cell Development」Immunity Volume 37, Issue 5, 785-799, 01 November 2012 USA PMID:23123060
^ Gershon RK and Kondo K.(1971)"Infectious immunological　tolerance."Immunology. 21,903-14. PMID 4943147
^ Sakaguchi S, Sakaguchi N, Asano M, Itoh M and Toda M.(1995)"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. 155,1151-64. PMID 7636184
^ Floess, S., Freyer, J., Siewert, C. et al.: Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol., 5, e38 (2007)／Ohkura, N., Hamaguchi, M., Morikawa, H. et al.: T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity, 37, 785-799 (2012)
^ Ochs HD, Ziegler SF and Torgerson TR.(2005)"FOXP3 acts as a rheostat of the immune response."Immunol.Rev. 203,156-164. PMID 15661028

wiki en

[Wiki en表示]

The regulatory T cells (Tregs), formerly known as suppressor T cells, are a subpopulation of T cells which modulate the immune system, maintain tolerance to self-antigens, and abrogate autoimmune disease. These cells generally suppress or downregulate induction and proliferation of effector T cells. Additional regulatory T cells known as Treg17 cells have recently been identified. Mouse models have suggested that modulation of Tregs can treat autoimmune disease and cancer, and facilitate organ transplantation.

Regulatory T cell populations

T regulatory cells are a component of the immune system that suppress immune responses of other cells. This is an important "self-check" built into the immune system to prevent excessive reactions. Regulatory T cells come in many forms with the most well-understood being those that express CD4, CD25, and Foxp3 (CD4+CD25+ regulatory T cells). These "Tregs" are different from helper T cells.^[1] Another regulatory T cell subset is Treg17 cells.^[2] Regulatory T cells are involved in shutting down immune responses after they have successfully eliminated invading organisms, and also in preventing autoimmunity cells.^[3]

CD4+ Foxp3+ regulatory T cells have been called "naturally-occurring" regulatory T cells to distinguish them from "suppressor" T cell populations that are generated in vitro. Additional regulatory T cell populations include Tr1, Th3, CD8+CD28-, and Qa-1 restricted T cells. The contribution of these populations to self-tolerance and immune homeostasis is less well defined. FOXP3 can be used as a good marker for mouse CD4+CD25+ T cells, although recent studies have also shown evidence for FOXP3 expression in CD4+CD25- T cells. In humans, FoxP3 is also expressed by recently activated conventional T-cells and thus does not specifically identify human T-reg.^[4]

Development

All T cells come from progenitor cells from the bone marrow, which become committed to their lineage in the thymus. All T cells begin as CD4-CD8-TCR- cells at the DN (double-negative) stage, where an individual cell will rearrange its T cell receptor genes to form a unique, functional molecule, which they, in turn, test against cells in the thymic cortex for a minimal level of interaction with self-MHC. If they receive these signals, they proliferate and express both CD4 and CD8, becoming double-positive cells. The selection of T_regs occurs on radio-resistant haemopoietically-derived MHC class II-expressing cells in the medulla or Hassal’s corpuscles in the thymus. At the DP (double-positive) stage, they are selected by their interaction with the cells within the thymus, begin the transcription of Foxp3, and become T_reg cells, although they may not begin to express Foxp3 until the single-positive stage, at which point they are functional T_regs. T_reg do not have the limited TCR expression of NKT or γδ T cells; T_reg have a larger TCR diversity than effector T cells, biased towards self-peptides.

The process of T_reg selection is determined by the affinity of interaction with the self-peptide MHC complex. Selection to become a T_reg is a “Goldilocks” process; T cell that receives very strong signals will undergo apoptotic death; a cell that receives a weak signal will survive and be selected to become an effector cell. If a T cell receives an intermediate signal, then it will become a regulatory cell. Due to the stochastic nature of the process of T cell activation, all T cell populations with a given TCR will end up with a mixture of T_eff and T_reg – the relative proportions determined by the affinities of the T cell for the self-peptide-MHC. Even in mouse models with TCR-transgenic cells selected on specific-antigen-secreting stroma, deletion or conversion is not complete.

Foxp3⁺ T_reg generation in the thymus is delayed by several days compared to T_eff cells and does not reach adult levels in either the thymus or periphery until around three weeks post-partum. T_reg cells require CD28 co-stimulation and B7.2 expression is largely restricted to the medulla, the development of which seems to parallel the development of Foxp3⁺ cells. It has been suggested that the two are linked, but no definitive link between the processes has yet been shown. TGF-β is not required for T_reg functionality, in the thymus, as thymic T_reg from TGF-β insensitive TGFβRII-DN mice are functional.

Function

The immune system must be able to discriminate between self and non-self. When self/non-self discrimination fails, the immune system destroys cells and tissues of the body and as a result causes autoimmune diseases. Regulatory T cells actively suppress activation of the immune system and prevent pathological self-reactivity, i.e. autoimmune disease. The critical role regulatory T cells play within the immune system is evidenced by the severe autoimmune syndrome that results from a genetic deficiency in regulatory T cells (IPEX syndrome - see also below).

The molecular mechanism by which regulatory T cells exert their suppressor/regulatory activity has not been definitively characterized and is the subject of intense research. In vitro experiments have given mixed results regarding the requirement of cell-to-cell contact with the cell being suppressed. The immunosuppressive cytokines TGF-beta and Interleukin 10 (IL-10) have also been implicated in regulatory T cell function.

Induced regulatory T cells

Induced Regulatory T (iTreg) cells (CD4⁺ CD25⁺ Foxp3⁺) are suppressive cells involved in tolerance. iTreg cells have been shown to suppress T cell proliferation and experimental autoimmune diseases. These cells include Treg17 cells. iTreg cells develop from mature CD4⁺ conventional T cells outside of the thymus: a defining distinction between natural regulatory T (nTreg) cells and iTreg cells. Though iTreg and nTreg cells share a similar function iTreg cells have recently been shown to be "an essential non-redundant regulatory subset that supplements nTreg cells, in part by expanding TCR diversity within regulatory responses".^[5] Acute depletion of the iTreg cell pool in mouse models has resulted in inflammation and weight loss. The contribution of nTreg cells versus iTreg cells in maintaining tolerance is unknown, but both are important. Epigenetic differences have been observed between nTreg and iTreg cells, with the former having more stable Foxp3 expression and wider demethylation.

Regulatory T cells and disease

An important question in the field of immunology is how the immunosuppressive activity of regulatory T cells is modulated during the course of an ongoing immune response. While the immunosuppressive function of regulatory T cells prevents the development of autoimmune disease, it is not desirable during immune responses to infectious microorganisms. Current hypotheses suggest that, upon encounter with infectious microorganisms, the activity of regulatory T cells may be downregulated, either directly or indirectly, by other cells to facilitate elimination of the infection. Experimental evidence from mouse models suggests that some pathogens may have evolved to manipulate regulatory T cells to immunosuppress the host and so potentiate their own survival. For example, regulatory T cell activity has been reported to increase in several infectious contexts, such as retroviral infections (the most well-known of which is HIV), mycobacterial infections (like tuberculosis), and various parasitic infections including Leishmania and malaria.

Studies of human subjects with a history of leishmania infection suggest that modulation of CD8⁺ suppressor T cells is, at least partly, mediated by cytokines. Leishmania specific CD4⁺ helper T cells predominate in adults with strong protective immunity (skin-test positive with no history of clinical infection). When added to autologous leishmania infected macrophages these T cells cause parasite death and secretion of large amounts of interferon-gamma and lymphotoxin. CD8⁺ T suppressor cells predominate in patients with no protective immunity (visceral leishmaniasis patients). When added to autologous peripheral blood mononuclear cells isolated after successful treatment, these T cells inhibit interferon-gamma secretion and proliferation and increase interleukin-6 and interleukin-10 secretion. A soluble factor(s) generated by antigen or phytohemagglutinin stimulation of leishmania-specific CD4⁺ helper T cells from skin-test positive adults killed CD8⁺ T cells but not CD4⁺ helper T cells when added to culture media. Soluble factors generated by antigen stimulation of peripheral blood mononuclear cells from skin-test positive adults prevented CD8⁺ suppressor T cell mediated increases in interleukin-10 secretion. These findings suggest that antigen stimulation of CD4⁺ helper T cells results in production of cytokines that kill or down regulate CD8⁺ T suppressor cells. Once the leishmania infection has been eliminated and leishmania antigens are gone, CD8⁺ T suppressor cells down-regulate CD4⁺ T helper cells. Isolation of cytokines that inhibit and kill CD8⁺ T suppressor cells might be useful in treating diseases that involve immune suppression such as leishmaniasis, AIDS, and certain cancers.^[6]^[7]

CD4⁺ Regulatory T cells are often associated with solid tumours in both humans and murine models. Increased numbers of regulatory T cells in breast, colorectal and ovarian cancers is associated with a poorer prognosis.^[8]

CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4⁺CD25− T cells.^[9]

Molecular characterization

Similar to other T cells, regulatory T cells develop in the thymus. The latest research suggests that regulatory T cells are defined by expression of the forkhead family transcription factor FOXP3 (forkhead box p3). Expression of FOXP3 is required for regulatory T cell development and appears to control a genetic program specifying this cell's fate.^[10] The large majority of Foxp3-expressing regulatory T cells are found within the major histocompatibility complex (MHC) class II restricted CD4-expressing (CD4⁺) population and express high levels of the interleukin-2 receptor alpha chain (CD25). In addition to the Foxp3-expressing CD4⁺ CD25⁺, there also appears to be a minor population of MHC class I restricted CD8⁺ Foxp3-expressing regulatory T cells. These Foxp3-expressing CD8⁺ T cells do not appear to be functional in healthy individuals but are induced in autoimmune disease states by T cell receptor stimulation to suppress IL-17-mediated immune responses.^[11] Unlike conventional T cells, regulatory T cells do not produce IL-2 and are therefore anergic at baseline.

A number of different methods are employed in research to identify and monitor T_reg cells. Originally, high expression of CD25 and CD4 surface markers was used (CD4⁺CD25⁺ cells). This is problematic as CD25 is also expressed on non-regulatory T cells in the setting of immune activation such as during an immune response to a pathogen. As defined by CD4 and CD25 expression, regulatory T cells comprise about 5-10% of the mature CD4⁺ T cell subpopulation in mice and humans, while about 1-2% of T_reg can be measured in whole blood. The additional measurement of cellular expression of Foxp3 protein allowed a more specific analysis of T_reg cells (CD4⁺CD25⁺Foxp3⁺ cells). However, Foxp3 is also transiently expressed in activated human effector T cells, thus complicating a correct T_reg analysis using CD4, CD25 and Foxp3 as markers in humans. Therefore, some research groups use another marker, the absence or low-level expression of the surface protein CD127 in combination with the presence of CD4 and CD25. Several additional markers have been described, e.g., high levels of CTLA-4 (cytotoxic T-lymphocyte associated molecule-4) and GITR (glucocorticoid-induced TNF receptor) are also expressed on regulatory T cells, however the functional significance of this expression remains to be defined. There is a great interest in identifying cell surface markers that are uniquely and specifically expressed on all Foxp3-expressing regulatory T cells. However, to date no such molecule has been identified.

In addition to the search for novel protein markers, a different method to analyze and monitor T_reg cells more accurately has been described in the literature. This method is based on DNA methylation analysis. Only in T_reg cells, but not in any other cell type, including activated effector T cells, a certain region within the foxp3 gene (TSDR, T_reg-specific-demethylated region) is found demethylated, which allows to monitor T_reg cells through a PCR reaction or other DNA-based analysis methods.^[12] Interplay between the Th17 cells and regulatory T cells are important in many diseases like respiratory diseases.^[13]

Recent evidence suggests that mast cells may be important mediators of T_reg-dependent peripheral tolerance.^[14]

Tregitopes

Tregitopes, or regulatory T cell epitopes, were discovered in 2008 and consist of linear sequences of amino acids contained within monoclonal antibodies and immunoglobulin G (IgG). Since their discovery, evidence has indicated Tregitopes may be crucial to the activation of natural regulatory T cells.^[15]^[16]^[16]^[17] Potential applications of Tregitopes have been hypothesized: tolerization to transplants, protein drugs, blood transfer therapies, and type I diabetes as well as reduction of immune response for the treatment of allergies.^[18]^[19]^[20]^[21]^[22]^[23]^[24]^[25]^[26]

Genetic deficiency

Genetic mutations in the gene encoding Foxp3 have been identified in both humans and mice based on the heritable disease caused by these mutations. This disease provides the most striking evidence that regulatory T cells play a critical role in maintaining normal immune system function. Humans with mutations in Foxp3 suffer from a severe and rapidly fatal autoimmune disorder known as Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome.^[27]^[28]

The IPEX syndrome is characterized by the development of overwhelming systemic autoimmunity in the first year of life, resulting in the commonly observed triad of watery diarrhea, eczematous dermatitis, and endocrinopathy seen most commonly as insulin-dependent diabetes mellitus. Most individuals have other autoimmune phenomena including Coombs-positive hemolytic anemia, autoimmune thrombocytopenia, autoimmune neutropenia, and tubular nephropathy. The majority of affected males die within the first year of life of either metabolic derangements or sepsis. An analogous disease is also observed in a spontaneous Foxp3-mutant mouse known as “scurfy”.

References

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^ Singh B, Schwartz JA, Sandrock C, Bellemore SM, Nikoopour E (2013). "Modulation of autoimmune diseases by interleukin (IL)-17 producing regulatory T helper (Th17) cells". Indian J Med Res. 138: 591–4. PMID 24434314.
^ Shevach EM (2000). "Regulatory T cells in autoimmmunity". Annu Rev Immunol 18: 423–49. doi:10.1146/annurev.immunol.18.1.423. PMID 10837065.
^ Sakaguchi S (2004). "Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses". Annu Rev Immunol 22: 531–62. doi:10.1146/annurev.immunol.21.120601.141122. PMID 15032588.
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^ Holaday BJ, Pompeu MM, Jeronimo S, Texeira MJ, Sousa Ade A, Vasconcelos AW, Pearson RD, Abrams JS, Locksley RM (December 1993). "Potential role for interleukin-10 in the immunosuppression associated with kala azar". J. Clin. Invest. 92 (6): 2626–32. doi:10.1172/JCI116878. PMC 288459. PMID 8254019.
^ Holaday BJ (1999). "Immunotherapy for visceral leishmaniasis: ability of factors produced during anti-leishmania responses of skin test positive adults to inhibit peripheral blood mononuclear cell activities associated with visceral leishmaniasis". Mem. Inst. Oswaldo Cruz 94 (1): 55–66. doi:10.1590/s0074-02761999000100013. PMID 10029912.
^ Dranoff G (December 2005). "The therapeutic implications of intratumoral regulatory T cells". Clin. Cancer Res. 11 (23): 8226–9. doi:10.1158/1078-0432.CCR-05-2035. PMID 16322278.
^ Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM (October 2007). "CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4⁺CD25 T cells". Blood 110 (7): 2537–44. doi:10.1182/blood-2007-03-082578. PMC 1988926. PMID 17615291.
^ Marson, Alexander et al. (2009). "Foxp3 occupancy and regulation of key target genes during T-cell stimulation". Nature 445 (?): 931–935. doi:10.1038/nature05478. PMC 3008159. PMID 17237765.
^ Ellis SD, McGovern JL, van Maurik A, Howe D, Ehrenstein MR, Notley CA. "Induced CD8+FoxP3+ Treg cells in rheumatoid arthritis are modulated by p38 phosphorylation and monocytes expressing membrane tumor necrosis factor α and CD86.". 2014. Arthritis Rheumatol. 66(10):2694-705. doi: 10.1002/art.38761. PMID 24980778
^ Wieczorek G, Asemissen A, Model F, Turbachova I, Floess S, Liebenberg V, Baron U, Stauch D, Kotsch K, Pratschke J, Hamann A, Loddenkemper C, Stein H, Volk HD, Hoffmüller U, Grützkau A, Mustea A, Huehn J, Scheibenbogen C, Olek S (January 2009). "Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue". Cancer Res. 69 (2): 599–608. doi:10.1158/0008-5472.CAN-08-2361. PMID 19147574.
^ Agarwal, A; Singh, M; Chatterjee, BP; Chauhan, A; Chakraborti, A (2014). "Interplay of T Helper 17 Cells with CD4(+)CD25(high) FOXP3(+) Tregs in Regulation of Allergic Asthma in Pediatric Patients.". International journal of pediatrics 2014: 636238. doi:10.1155/2014/636238. PMID 24995020.
^ Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K, Scott ZA, Coyle AJ, Reed JL, Van Snick J, Strom TB, Zheng XX, Noelle RJ (August 2006). "Mast cells are essential intermediaries in regulatory T-cell tolerance". Nature 442 (7106): 997–1002. doi:10.1038/nature05010. PMID 16921386.
^ Tregitopes can dampen unwanted immune responses through selective activation. "Tregitopes". EpiVax, Inc. Retrieved July 2013.
^ ^a ^b . Molecular Therapy http://www.nature.com/mt/journal/vaop/naam/abs/mt2013166a.html. Retrieved July 2013. Missing or empty |title= (help)
^ (PDF). Blood Journal http://www.epivax.com/wp-content/uploads/2013/02/DeGroot_Tregitope_Blood_2008.pdf. Retrieved July 2013. Missing or empty |title= (help)
^ "New $2.25M infusion of NIH funds for EpiVax' Tregitope, proposed "Paradigm-Shifting" Treatment". Fierce Biotech Research. Retrieved July 2013.
^ Su Y, Rossi R, De Groot AS, Scott DW (August 2013). "Regulatory T cell epitopes (Tregitopes) in IgG induce tolerance in vivo and lack immunogenicity per se". J. Leukoc. Biol. (Journal of Leukocyte Biology) 94 (2): 377–83. doi:10.1189/jlb.0912441. PMID 23729499.
^ Cousens, LP; Su, Y; McClaine, E; Li, X; Terry, F; Smith, R; Lee, J; Martin, W; Scott, DW; De Groot, Anne S. (2013). "Application of IgG-Derived Natural Treg Epitopes (IgG Tregitopes) to Antigen-Specific Tolerance Induction in a Murine Model of Type 1 Diabetes". Journal of Diabetes Research (Journal of Diabetes Research) 2013: 621693. doi:10.1155/2013/621693. PMC 3655598. PMID 23710469.
^ (PDF). Human Vaccines & Immunotherapeutics http://www.epivax.com/wp-content/uploads/2013/02/Tregitope_Teaching-Tolerence_Pompe_Disease.pdf. Retrieved July 2013. Missing or empty |title= (help)
^ (PDF). Journal of Clinical Immunology http://www.epivax.com/wp-content/uploads/2013/02/Tregitope-Clinical-Immunology-2012.pdf. Retrieved July 2013. Missing or empty |title= (help)
^ (PDF). Autoimmunity Reviews http://www.epivax.com/wp-content/uploads/2013/02/Tregitope-update_Autoimmunity-Reviews-2012.pdf. Retrieved July 2013. Missing or empty |title= (help)
^ (PDF). World Journal of Gastroenterology http://www.epivax.com/wp-content/uploads/2013/02/Adeno-associated-virus-mediated-delivery-of-Tregitope-167-2012.pdf. Retrieved July 2013. Missing or empty |title= (help)
^ (PDF). Neurology Research International http://www.epivax.com/wp-content/uploads/2013/02/Tregitopes_MS_DeGroot_2011.pdf. Retrieved July 2013. Missing or empty |title= (help)
^ (PDF). Blood Journal http://www.epivax.com/wp-content/uploads/2013/02/DeGroot_Tregitope_Blood_2008.pdf. Retrieved July 2013. Missing or empty |title= (help)
^ Online Mendelian Inheritance in Man IPEX
^ ipex at NIH/UW GeneTests

External links

Regulatory T-Cells at the US National Library of Medicine Medical Subject Headings (MeSH)

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1. ヘルパーT細胞サブセット：疾患における分化および役割 t helper subsets differentiation and role in disease
2. 適応細胞性免疫応答 the adaptive cellular immune response
3. 癌免疫療法の原則 principles of cancer immunotherapy
4. BおよびTリンパ球の正常な発生 normal b and t lymphocyte development
5. 免疫系におけるサイトカインの役割 role of cytokines in the immune system

English Journal

Assessment of Treg/Th17 axis role in immunopathogenesis of chronic injuries of mustard lung disease.

Imani S1, Salimian J1, Bozorgmehr M2, Vahedi E1, Ghazvini A1, Ghanei M1, Panahi Y1.
Journal of receptor and signal transduction research.J Recept Signal Transduct Res.2016 Oct;36(5):531-41. doi: 10.3109/10799893.2016.1141953. Epub 2016 Feb 19.
PURPOSE: Sulfur mustard (SM) lung is a heterogeneous disease associated with abnormal inflammatory immune responses. The Th17/Treg axis imbalance is associated with the pathogenesis of chronic inflammatory pulmonary disease. We aimed to determine the distribution of different Th17 and Treg cells in
PMID 26895417

Circulating regulatory T cells in patients with aortic valve stenosis: Association with disease progression and aortic valve intervention.

Shimoni S1, Bar I2, Meledin V2, Gandelman G2, George J2.
International journal of cardiology.Int J Cardiol.2016 Sep 1;218:181-7. doi: 10.1016/j.ijcard.2016.05.039. Epub 2016 May 14.
BACKGROUND: Severe aortic valve stenosis (AS) accounts for considerable morbidity and death, especially in older patients. There is increasing evidence to suggest a role for immune modulating cells in aortic valve (AV) degeneration. Regulatory T cells (Tregs) tune down inflammation. We aimed to stud
PMID 27236112

IL17 producing γδT cells induce angiogenesis and are associated with poor survival in gallbladder cancer patients.

Sudam Patil R1, Umesh Shah S1, Vinayak Shrikhande S2, Goel M2, Prabhakar Dikshit R3, Vivek Chiplunkar S1.
International journal of cancer.Int J Cancer.2016 Aug 15;139(4):869-81. doi: 10.1002/ijc.30134. Epub 2016 Apr 26.
Despite conventional treatment modalities, gallbladder cancer (GBC) remains a highly lethal malignancy. Prognostic biomarkers and effective adjuvant immunotherapy for GBC are not available. In the recent past, immunotherapeutic approaches targeting tumor associated inflammation have gained importanc
PMID 27062572

Japanese Journal

腫瘍局所の免疫抑制機構 (特集免疫チェックポイントの基礎と臨床)

加藤真吾,寺部正記
最新医学 70(3), 343-347, 2015-03
NAID 40020387550

免疫(1)自然免疫と獲得免疫

八木淳二
東京女子医科大学雑誌 85(1), 1-8, 2015-02-25
… それに対処するために、制御性T細胞 (regulatory T cells, Treg cells)が自己免疫応答を抑制する働きを担っている。 … この場合も、Treg cellが重要な役割を果たしていることが明らかにされている。 …
NAID 110009883329

FoxP3+ regulatory T cells in the peripheral blood and synovial fluid of patients with rheumatoid arthritis

, ,
Inflammation and Regeneration 35(2), 051-056, 2015
… Human regulatory T (Treg) cells expressing the transcription factor forkhead box P3 (FoxP3) are indispensable for self-tolerance and immune homeostasis. … Abnormal Treg cell counts and impaired function have been implicated in the development of various autoimmune diseases. … The Treg cell counts in the peripheral blood of subjects with rheumatoid arthritis (RA) vary, probably due to heterogeneity of the Treg cells. …
NAID 130005063947