同: Cytotoxic T lymphocyte-associated protein-4

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/09/26 02:18:29」(JST)

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CTLA4 or CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152 (cluster of differentiation 152), is a protein receptor that downregulates the immune system. CTLA4 is found on the surface of T cells, which lead the cellular immune attack on antigens. The T cell attack can be turned on by stimulating the CD28 receptor on the T cell. The T cell attack can be turned off by stimulating the CTLA4 receptor, which acts as an "off" switch.

In humans, the CTLA4 protein is encoded by the CTLA4 gene.^[1]

Function and mechanism

CTLA4 is a member of the immunoglobulin superfamily, which is expressed on the surface of Helper T cells and transmits an inhibitory signal to T cells. CTLA4 is similar to the T-cell co-stimulatory protein, CD28, and both molecules bind to CD80 and CD86, also called B7-1 and B7-2 respectively, on antigen-presenting cells. CTLA4 transmits an inhibitory signal to T cells,^[2]^[3]^[4]^[5] whereas CD28 transmits a stimulatory signal.^[6]^[7] Intracellular CTLA4 is also found in regulatory T cells and may be important to their function. T cell activation through the T cell receptor and CD28 leads to increased expression of CTLA-4, an inhibitory receptor for B7 molecules.

The mechanism by which CTLA-4 acts in T cells remains somewhat controversial. Biochemical evidence suggested that CTLA-4 recruited a phosphatase to the T cell receptor, thus attenuating the signal^[8] This work remains unconfirmed in the literature since its first publication. More recent work has suggested that CTLA-4 may function in vivo by capturing and removing B7-1 and B7-2 from the membranes of antigen-presenting cells, thus making these unavailable for triggering of CD28 ^[9]

CTLA-4 may also function via modulation of cell motility and/or signaling through PI3 kinase.^[10] Early multiphoton microscopy studies observing T-cell motility in intact lymph nodes appeared to give evidence for the so-called ‘reverse-stop signaling model’.^[11] In this model CTLA 4 reverses the TCR-induced ‘stop signal’ needed for firm contact between T cells and antigen-presenting cells (APCs).^[12] However, those studies compared CTLA-4 positive cells, which are predominantly regulatory cells and are at least partially activated, with CTLA-4 negative naive T cells. The disparity of these cells in multiple regards may explain some of these results. Other groups who have analyzed the effect of antibodies to CTLA-4 in vivo have concluded little or no effect upon motility ^[13] Recent evidence also suggests that antibodies to CTLA-4 may exert additional effects when used in vivo, by binding and thereby depleting regulatory T cells ^[14]

Structure

The protein contains an extracellular V domain, a transmembrane domain, and a cytoplasmic tail. Alternate splice variants, encoding different isoforms, have been characterized. The membrane-bound isoform functions as a homodimer interconnected by a disulfide bond, while the soluble isoform functions as a monomer. The intracellular domain is similar to that of CD28, in that it has no intrinsic catalytic activity and contains one YVKM motif able to bind PI3K, PP2A and SHP-2 and one proline-rich motif able to bind SH3 containing proteins. The first role of CTLA-4 in inhibiting T cell responses seem to be directly via SHP-2 and PP2A dephosphorylation of TCR-proximal signalling proteins such as CD3 and LAT. CTLA-4 can also affect signalling indirectly via competing with CD28 for CD80/86 binding. CTLA-4 can also bind PI3K, although the importance and results of this interaction are uncertain.

Clinical significance

Mutations in this gene have been associated with insulin-dependent diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy, primary biliary cirrhosis and other autoimmune diseases.

Polymorphisms of the CTLA-4 gene are associated with autoimmune diseases such as autoimmune thyroid disease and multiple sclerosis, though this association is often weak. In Systemic Lupus Erythematosus (SLE), the splice variant sCTLA-4 is found to be aberrantly produced and found in the serum of patients with active SLE.

Agonists to reduce immune activity

The comparatively higher binding affinity of CTLA4 has made it a potential therapy for autoimmune diseases. It plays a role in the initial immune response to and infection of immune cells by, HIV, along with the PD-1 pathway and others. Fusion proteins of CTLA4 and antibodies (CTLA4-Ig) have been used in clinical trials for rheumatoid arthritis.^[15] The fusion protein CTLA4-Ig is commercially available as Orencia (abatacept). A second generation form of CTLA4-Ig known as belatacept was recently approved by the FDA based on favorable results from the randomized Phase III BENEFIT (Belatacept Evaluation of Nephroprotection and Efficacy as First Line Immunosuppression) study. It was approved for renal transplantation in patients that are sensitized to EBV, or Epstein Barr Virus.

Antagonists to increase immune activity

Conversely, there is increasing interest in the possible therapeutic benefits of blocking CTLA4 (using antagonistic antibodies against CTLA such as ipilimumab (FDA approved for melanoma in 2011) as a means of inhibiting immune system tolerance to tumours and thereby providing a potentially useful immunotherapy strategy for patients with cancer. This is the first approved immune checkpoint blockade therapy.^[16]

Interactions

CTLA-4 has been shown to interact with:

AP2M1,^[17]^[18]
CD80,^[19]^[20]
CD86,
SHP-2, and
PPP2R5A. ^[21]

References

^ Dariavach P, Mattéi MG, Golstein P, Lefranc MP (December 1988). "Human Ig superfamily CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains". Eur. J. Immunol. 18 (12): 1901–5. doi:10.1002/eji.1830181206. PMID 3220103.
^ Krummel, M.F., and Allison, J.P. (1995). CD28 and CTLA-4 deliver opposing signals which regulate the response of T cells to stimulation. Journal of Experimental Medicine 182, 459-465.
^ Walunas, T.L., Bakker, C.Y., and Bluestone, J.A. (1996). CTLA-4 ligation blocks CD28-dependent T cell activation. Journal of Experimental Medicine 183, 2541-2550.
^ Walunas, T.L., Lenschow, D.J., Bakker, C.Y., Linsley, P.S., Freeman, G.J., Green, J.M., Thompson, C.B., and Bluestone, J.A. (1994) CTLA-4 can function as a negative regulator of T cell activation. Immunity 1, 405-413.
^ Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW (November 1995). "Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4". Science 270 (5238): 985–8. doi:10.1126/science.270.5238.985. PMID 7481803.
^ Harding, F., McArthur, J.G., Gross, J.A., Raulet, D.H., and Allison, J.P. (1992). CD28 mediated signalling costimulates murine T cells and prevents the induction of anergy in T cell clones. Nature 356, 607-609.
^ Magistrelli G, Jeannin P, Herbault N, Benoit De Coignac A, Gauchat JF, Bonnefoy JY, Delneste Y (November 1999). "A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells". Eur. J. Immunol. 29 (11): 3596–602. doi:10.1002/(SICI)1521-4141(199911)29:11<3596::AID-IMMU3596>3.0.CO;2-Y. PMID 10556814.
^ Lee, K.-M., Chuang, E., Griffin, M., Khattri, R., Hong, D.K., Zhang, W., Straus, D., Samelson, L.E., Thompson, C.B., and Bluestone, J.A. (1998). Molecular basis of T cell inactivation by CTLA-4. Science 282, 2263-2266.
^ Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, Baker J, Jeffery LE, Kaur S, Briggs Z, Hou TZ, Futter CE, Anderson G, Walker LS, Sansom DM.Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science. 2011 Apr 29;332(6029):600-3
^ Knieke K, Lingel H, Chamaon K, Brunner-Weinzierl MC. Migration of Th1 lymphocytes is regulated by CD152 (CTLA-4)-mediated signaling via PI3 kinase-dependent Akt activation. PLoS One. 2012;7(3):e31391
^ Schneider H, Downey J, Smith A, Zinselmeyer BH, Rush C, Brewer JM, Wei B, Hogg N, Garside P, Rudd CE (September 2006). "Reversal of the TCR stop signal by CTLA-4". Science 313 (5795): 1972–5. doi:10.1126/science.1131078. PMID 16931720.
^ Rudd CE, Taylor A, Schneider H (May 2009). "CD28 and CTLA-4 coreceptor expression and signal transduction". Immunol. Rev. 229 (1): 12–26. doi:10.1111/j.1600-065X.2009.00770.x. PMID 19426212.
^ Fife, B.T., Pauken, K.E., Eagar, T.N., Obu, T., Wu, J., Tang, Q., Azuma, M., Krummel, M.F., and Bluestone, J.A. (2009). Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol 10, 1185-1192.
^ Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, Roddie C, Henry JY, Yagita H, Wolchok JD, Peggs KS, Ravetch JV, Allison JP, Quezada SA.Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med. 2013 Aug 26;210(9):1695-710
^ Arthritis Research & Therapy | Meeting Abstract | Abatacept (CTLA4Ig) treatment increases the remission rate in rheumatoid arthritis patients refractory to methotrexate treatment
^ Pardoll DM (April 2012). "The blockade of immune checkpoints in cancer immunotherapy". Nat. Rev. Cancer 12 (4): 252–64. doi:10.1038/nrc3239. PMID 22437870.
^ Follows ER, McPheat JC, Minshull C, Moore NC, Pauptit RA, Rowsell S, Stacey CL, Stanway JJ, Taylor IW, Abbott WM (October 2001). "Study of the interaction of the medium chain mu 2 subunit of the clathrin-associated adapter protein complex 2 with cytotoxic T-lymphocyte antigen 4 and CD28". Biochem. J. 359 (Pt 2): 427–34. doi:10.1042/0264-6021:3590427. PMC 1222163. PMID 11583591.
^ Chuang E, Alegre ML, Duckett CS, Noel PJ, Vander Heiden MG, Thompson CB (July 1997). "Interaction of CTLA-4 with the clathrin-associated protein AP50 results in ligand-independent endocytosis that limits cell surface expression". J. Immunol. 159 (1): 144–51. PMID 9200449.
^ Peach RJ, Bajorath J, Naemura J, Leytze G, Greene J, Aruffo A, Linsley PS (September 1995). "Both extracellular immunoglobin-like domains of CD80 contain residues critical for binding T cell surface receptors CTLA-4 and CD28". J. Biol. Chem. 270 (36): 21181–7. doi:10.1074/jbc.270.36.21181. PMID 7545666.
^ Stamper CC, Zhang Y, Tobin JF, Erbe DV, Ikemizu S, Davis SJ, Stahl ML, Seehra J, Somers WS, Mosyak L (March 2001). "Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses". Nature 410 (6828): 608–11. doi:10.1038/35069118. PMID 11279502.
^ Baroja ML, Vijayakrishnan L, Bettelli E, Darlington PJ, Chau TA, Ling V, Collins M, Carreno BM, Madrenas J, Kuchroo VK (May 2002). "Inhibition of CTLA-4 function by the regulatory subunit of serine/threonine phosphatase 2A". J. Immunol. 168 (10): 5070–8. doi:10.4049/jimmunol.168.10.5070. PMID 11994459.

UpToDate Contents

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1. 進行黒色腫に対する免疫チェックポイント分子阻害による免疫療法 immunotherapy of advanced melanoma with immune checkpoint inhibition
2. 去勢抵抗性前立腺癌に対する免疫療法 immunotherapy for castration resistant prostate cancer
3. 関節リウマチのT細胞標的療法 t cell targeted therapies for rheumatoid arthritis
4. 抗原提示細胞 antigen presenting cells
5. 移植免疫 transplantation immunobiology

English Journal

Alteration in Frequency and Function of CD4+CD25+FOXP3+ Regulatory T cells in Patients with Immune Thrombocytopenic Purpura.

Arandi N, Mirshafiey A, Jeddi-Tehrani M, Shaghaghi M, Sadeghi B, Abolhassani H, Sharifian RA, Rahiminejad MS, Aghamohammadi A.Author information Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. nargess_786@yahoo.com.AbstractImmune thrombocytopenic purpura (ITP) is an autoimmune bleeding disorder characterized by production of auto-antibodies against platelet antigens. It is obvious that regulatory T cells (Tregs) have a major role in controlling immune homeostasis and preventing autoimmunity.To investigate the frequency and functions of Tregs, twenty ITP patients and twenty age- and sex-matched healthy controls were recruited. The peripheral blood mononuclear cells were isolated and the proportion of Tregs was defined by flow cytometry method. The expression of immune-regulatory markers, cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and glucocorticoid induced tumor necrosis factor receptor (GITR) were also assessed by quantitative Real-time PCR TaqMan method. For evaluation of Treg function, Tregs were enriched and their ability to inhibit proliferation of T cells was measured and levels of immune-regulatory cytokines IL-10 and TGF-β were also measured.Results showed that the frequency of Tregs and the mean fluorescence intensity of FOXP3 protein significantly decreased in ITP patients compared to those in healthy controls. In addition, there was a significant reduction in relative expression of both CTLA-4 and GITR mRNA in ITP patients (P=0.02 and P=0.006, respectively). The suppressive function of Tregs also diminished in ITP patients compared to that in controls. Both IL-10 and TGF-β cytokines were produced in lower amounts in ITP patients than controls.It could be concluded that alteration in Treg frequency and functional characteristics might be responsible for loss of self-tolerance and subsequently destructive immune responses observed in ITP patients.
Iranian journal of allergy, asthma, and immunology.Iran J Allergy Asthma Immunol.2014 Apr;13(2):85-92.
Immune thrombocytopenic purpura (ITP) is an autoimmune bleeding disorder characterized by production of auto-antibodies against platelet antigens. It is obvious that regulatory T cells (Tregs) have a major role in controlling immune homeostasis and preventing autoimmunity.To investigate the frequenc
PMID 24338252

Targeting CD28 to prevent transplant rejection.

Yeung MY, Najafian N, Sayegh MH.Author information Brigham and Women's Hospital, Transplantation Research Center, Harvard Medical School, Renal Division , Boston, MA , USA +1 617 525 8005 ; +1 617 732 5254 ; myeung@rics.bwh.harvard.edu.AbstractIntroduction: The pivotal role of costimulatory pathways in regulating T-cell activation versus tolerance has stimulated tremendous interest in their manipulation for therapeutic purposes. Of these, the CD28-B7 pathway is arguably the most important and best studied. Therapeutic targets of CD28 are currently used in the treatment of melanoma, autoimmune diseases and in transplantation. Areas covered: In this review, we summarize our current knowledge of CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) signaling, and review the current state and challenges of harnessing them to promote transplant tolerance. Expert opinion: Despite the success of belatacept, a first-in-class CTLA-4 fusion protein now clinically used in transplantation, it is apparent that we have only scratched the surface in understanding the complexities of how costimulatory pathways modulate the immune system. Our initial assumption that positive costimulators activate effector T cells and prevent tolerance, while negative costimulators inhibit effector T cells and promote tolerance, is clearly an oversimplified view. Indeed, belatacept is not only capable of blocking deleterious CD28-B7 interactions that promote effector T-cell responses but can also have undesired effects on tolerogenic regulatory T-cell populations.
Expert opinion on therapeutic targets.Expert Opin Ther Targets.2014 Feb;18(2):225-42. doi: 10.1517/14728222.2014.863875. Epub 2013 Dec 12.
Introduction: The pivotal role of costimulatory pathways in regulating T-cell activation versus tolerance has stimulated tremendous interest in their manipulation for therapeutic purposes. Of these, the CD28-B7 pathway is arguably the most important and best studied. Therapeutic targets of CD28 are
PMID 24329604

Association of glutathione S-transferase M1/T1 polymorphisms with susceptibility to vitiligo.

Lu L1, Wu W2, Tu Y2, Yang Z2, He L3, Guo M4.Author information 1Department of Physiology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China.2Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.3Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China. Electronic address: heli2661@163.com.4Division of Science and Technology, Kunming Medical University, Kunming, Yunnan, China. Electronic address: glassgreen@163.com.AbstractBACKGROUND: Some studies suggested that Glutathione S-transferases M1/T1(GSTM1/T1) null polymorphisms may be associated with the risk of vitiligo.
Gene.Gene.2014 Feb 1;535(1):12-6. doi: 10.1016/j.gene.2013.11.024. Epub 2013 Dec 1.
BACKGROUND: Some studies suggested that Glutathione S-transferases M1/T1(GSTM1/T1) null polymorphisms may be associated with the risk of vitiligo.AIMS: The purpose of this study is to further evaluate the association between GSTM1/T1 null polymorphisms and the susceptibility to vitiligo.METHODS: We
PMID 24295891

Japanese Journal

MHC class II-independent and -dependent T cell expansion and B cell hyperactivity in vivo in mice deficient in CD152 (CTLA-4)

STOHL William,XU Dong,KIM Kyoung Soo,DAVID Chella S.,ALLISON James P.
International immunology 16(7), 895-904, 2004-07-01
NAID 10013291444

ddYマウスに自然発症するIgA腎症に対する可溶性CTLA-4の作用

OKANO Kazuhiro,NITTA Kosaku,HORITA Shigeru,ABE Ryo,NIHEI Hiroshi,岡野一祥,新田孝作,堀田茂,安部良,二瓶宏
東京女子医科大学雑誌 71(7/8), 377-386, 2001-08-25
… co-stimulatory signalの役割を解析することを目的とした.ddYマウスは,ヒトにおけるIgA腎症に類似した糸球体腎炎を自然発症するモデルマウスとして使用されている.今回の研究では,B7.1(CD80)とB7.2(CD86)に結合するCTLA-4(CD152)のfusion proteinを使用して,CD28-B7経路を阻害することにより,本モデルマウスにおける糸球体腎炎が抑制されるか否かについて検討した.各グループ(n=4)に対し,ヒトIgGのFcドメインのfusion protein(CTLA-4Ig)またはコント …
NAID 120002367707

ddYマウスに自然発症するIgA腎症に対する可溶性CTLA-4の作用

岡野一祥,新田孝作,堀田茂,安部良,二瓶宏
東京女子医科大学雑誌 71(7/8), 377-386, 2001-08-25
… co-stimulatory signalの役割を解析することを目的とした.ddYマウスは,ヒトにおけるIgA腎症に類似した糸球体腎炎を自然発症するモデルマウスとして使用されている.今回の研究では,B7.1(CD80)とB7.2(CD86)に結合するCTLA-4(CD152)のfusion proteinを使用して,CD28-B7経路を阻害することにより,本モデルマウスにおける糸球体腎炎が抑制されるか否かについて検討した.各グループ(n=4)に対し,ヒトIgGのFcドメインのfusion protein(CTLA-4Ig)またはコント …
NAID 110007526340

Related Pictures

Philips CD152 CD152 VERY DARK OLIVE AMBER B GLASS Marantz CD152 CD152 - MST-Design Wassertransferdruck Mouse CD152 (CTLA-4) Antibody APC UC10-4B9

★リンクテーブル★

リンク元	「CTLA-4」「CD28」
関連記事	「CD1」「CD15」

「CTLA-4」

Cytotoxic T-lymphocyte-associated protein 4
	; Structure of murine CTLA4 (CD152)
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1AH1, 1H6E, 1I85, 1I8L, 2X44, 3BX7, 3OSK
Identifiers
Symbols	CTLA4 ; CD; CD152; CELIAC3; CTLA-4; GRD4; GSE; IDDM12
External IDs	OMIM: 123890 MGI: 88556 HomoloGene: 3820 GeneCards: CTLA4 Gene
Gene ontology
Molecular function	• protein binding;
Cellular component	• Golgi apparatus; • plasma membrane; • integral component of plasma membrane; • external side of plasma membrane; • clathrin-coated endocytic vesicle; • perinuclear region of cytoplasm;
Biological process	• immune response; • cellular response to DNA damage stimulus; • negative regulation of B cell proliferation; • T cell costimulation; • negative regulation of T cell proliferation; • positive regulation of apoptotic process; • negative regulation of regulatory T cell differentiation; • negative regulation of immune response; • B cell receptor signaling pathway;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	This box: view; talk; edit;

　　[★]

同: cytotoxic T lymphocyte antigen-4, CD152, CTLA4
関: CD28

CTLA-4はCD28と同じファミリーであり、配列レベルで似ている。
CTLA-4はCD28と同様にT細胞系列で発現する。
CTLA-4はCD28と同様にAPCに発現しているB7(CD80/CD88)に結合する。
CTLA-4はCD28に比べ20倍以上のavidityがある (IMM.346)
CTLA-4にB7が結合すると、T細胞の活性化を抑制するように働く。すなわちCD28の反対の作用を呈する。
naive T細胞がAPCから抗原を提示され、co-stumilatory signalを受けとると、増殖・分化、IL-2の産生をおこなう。しかし、いったん活性化すると、IL-2の過剰産生を避けるためにT細胞ではCTLA-4を産生し、過剰なT細胞の増殖を抑制する。

「CD28」

　　[★]

同: Tp44
関: CTLA-4(CD152)

発現組織

T細胞サブセット、活性化B細胞

機能

naive T細胞の活性化(APC上のB7(CD80/CD88)に結合した副刺激のレセプター)

ファミリー

免疫グロブリン

「CD1」

　　[★]

同: leucine-6, CD1A through E

種類

CD1a, CD1b, CD1c, CD1d

発現組織

胸腺皮質、ランゲルハンス細胞、樹状細胞、B細胞(CD1c)、腸上皮、平滑筋、血管上皮(CD1d)

分子量

43-49

機能

MHC class I-like molecule, associated with β2-microgloulin. Has specialized role in presentation of lipid antigens

「CD15」

　　[★]

発現細胞

好中球、好酸球、単球

機能

糖脂質や多くの細胞表面糖タンパクに発現している末端の3糖

別名

Lewis^x, Le^x

[pmid3220103-1] Dariavach P, Mattéi MG, Golstein P, Lefranc MP (December 1988). "Human Ig superfamily CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains". Eur. J. Immunol. 18 (12): 1901–5. doi:10.1002/eji.1830181206. PMID 3220103.

[2] Krummel, M.F., and Allison, J.P. (1995). CD28 and CTLA-4 deliver opposing signals which regulate the response of T cells to stimulation. Journal of Experimental Medicine 182, 459-465.

[3] Walunas, T.L., Bakker, C.Y., and Bluestone, J.A. (1996). CTLA-4 ligation blocks CD28-dependent T cell activation. Journal of Experimental Medicine 183, 2541-2550.

[4] Walunas, T.L., Lenschow, D.J., Bakker, C.Y., Linsley, P.S., Freeman, G.J., Green, J.M., Thompson, C.B., and Bluestone, J.A. (1994) CTLA-4 can function as a negative regulator of T cell activation. Immunity 1, 405-413.

[pmid7481803-5] Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW (November 1995). "Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4". Science 270 (5238): 985–8. doi:10.1126/science.270.5238.985. PMID 7481803.

[6] Harding, F., McArthur, J.G., Gross, J.A., Raulet, D.H., and Allison, J.P. (1992). CD28 mediated signalling costimulates murine T cells and prevents the induction of anergy in T cell clones. Nature 356, 607-609.

[pmid10556814-7] Magistrelli G, Jeannin P, Herbault N, Benoit De Coignac A, Gauchat JF, Bonnefoy JY, Delneste Y (November 1999). "A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells". Eur. J. Immunol. 29 (11): 3596–602. doi:10.1002/(SICI)1521-4141(199911)29:11<3596::AID-IMMU3596>3.0.CO;2-Y. PMID 10556814.

[8] Lee, K.-M., Chuang, E., Griffin, M., Khattri, R., Hong, D.K., Zhang, W., Straus, D., Samelson, L.E., Thompson, C.B., and Bluestone, J.A. (1998). Molecular basis of T cell inactivation by CTLA-4. Science 282, 2263-2266.

[9] Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, Baker J, Jeffery LE, Kaur S, Briggs Z, Hou TZ, Futter CE, Anderson G, Walker LS, Sansom DM.Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science. 2011 Apr 29;332(6029):600-3

[10] Knieke K, Lingel H, Chamaon K, Brunner-Weinzierl MC. Migration of Th1 lymphocytes is regulated by CD152 (CTLA-4)-mediated signaling via PI3 kinase-dependent Akt activation. PLoS One. 2012;7(3):e31391

[pmid16931720-11] Schneider H, Downey J, Smith A, Zinselmeyer BH, Rush C, Brewer JM, Wei B, Hogg N, Garside P, Rudd CE (September 2006). "Reversal of the TCR stop signal by CTLA-4". Science 313 (5795): 1972–5. doi:10.1126/science.1131078. PMID 16931720.

[pmid19426212-12] Rudd CE, Taylor A, Schneider H (May 2009). "CD28 and CTLA-4 coreceptor expression and signal transduction". Immunol. Rev. 229 (1): 12–26. doi:10.1111/j.1600-065X.2009.00770.x. PMID 19426212.

[13] Fife, B.T., Pauken, K.E., Eagar, T.N., Obu, T., Wu, J., Tang, Q., Azuma, M., Krummel, M.F., and Bluestone, J.A. (2009). Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol 10, 1185-1192.

[14] Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, Roddie C, Henry JY, Yagita H, Wolchok JD, Peggs KS, Ravetch JV, Allison JP, Quezada SA.Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med. 2013 Aug 26;210(9):1695-710

[15] Arthritis Research & Therapy | Meeting Abstract | Abatacept (CTLA4Ig) treatment increases the remission rate in rheumatoid arthritis patients refractory to methotrexate treatment

[Pardoll_2012-16] Pardoll DM (April 2012). "The blockade of immune checkpoints in cancer immunotherapy". Nat. Rev. Cancer 12 (4): 252–64. doi:10.1038/nrc3239. PMID 22437870.

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[pmid7545666-19] Peach RJ, Bajorath J, Naemura J, Leytze G, Greene J, Aruffo A, Linsley PS (September 1995). "Both extracellular immunoglobin-like domains of CD80 contain residues critical for binding T cell surface receptors CTLA-4 and CD28". J. Biol. Chem. 270 (36): 21181–7. doi:10.1074/jbc.270.36.21181. PMID 7545666.

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CD152

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Function and mechanism

Structure

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Agonists to reduce immune activity

Antagonists to increase immune activity

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「CTLA-4」

「CD28」

発現組織

機能

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「CD1」

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分子量

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「CD15」

発現細胞

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