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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/04/01 03:00:28」(JST)

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CTLA-4 (Cytotoxic T-Lymphocyte Antigen 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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

CTLA-4 has been shown to interact with:

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

References[edit]

^ 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. PMID 11994459.

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2. 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
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English Journal

Differences in B7 and CD28 family gene expression in the peripheral blood between newly diagnosed young-onset and adult-onset type 1 diabetes patients.

Pruul K1, Kisand K1, Alnek K1, Metsküla K1, Reimand K1, Heilman K2, Peet A3, Varik K4, Peetsalu M4, Einberg Ü5, Tillmann V3, Uibo R6.
Molecular and cellular endocrinology.Mol Cell Endocrinol.2015 Sep 5;412:265-71. doi: 10.1016/j.mce.2015.05.012. Epub 2015 May 14.
Type-1 diabetes (T1D) is a heterogeneous autoimmune disease, and there are pathogenetic differences between young- and adult-onset T1D patients. We hypothesized that the expressions of genes involved in costimulatory immune system pathways in peripheral blood are differently regulated in young- and
PMID 25980680

Lack of association between cytotoxic T-lymphocyte antigen-4+49A/G polymorphism and psoriasis and vitiligo: A meta-analysis of case-control studies.

Liang J1, Zhang S1, Luo Q1, Li W1, Tian X1, Zhang F2, Zhao T1, Chen X1, Zhang X3.
Gene.Gene.2015 Sep 1;568(2):196-202. doi: 10.1016/j.gene.2015.05.051. Epub 2015 May 24.
BACKGROUND: Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a critical negative regulator of T-cell activation and proliferation. Several studies have assessed the association between CTLA-4+49A/G polymorphism and psoriasis and vitiligo, but the results are inconsistent.AIMS: This study was conducted t
PMID 26013045

Radiotherapy combined with immune checkpoint blockade immunotherapy: Achievements and challenges.

Teng F1, Kong L1, Meng X1, Yang J1, Yu J2.
Cancer letters.Cancer Lett.2015 Aug 28;365(1):23-9. doi: 10.1016/j.canlet.2015.05.012. Epub 2015 May 14.
To date, several kinds of immunomodulating monoclonal antibodies (mAbs) have been applied in clinical trials, such as anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) mAb and anti-programmed death-1 (anti-PD-1) mAb. With the recent success of cancer immunotherapy, especially the checkpoint inhibi
PMID 25980820

Japanese Journal

アバタセプト (特集関節リウマチ : ケアからキュアを目指した治療) -- (薬物治療とその留意点)

中村武,松原司
日本臨床 71(7), 1232-1237, 2013-07
NAID 40019711683

悪性黒色腫の抗体治療 (特集固形がんの免疫・抗体療法 : 基礎研究の進歩と臨床応用) -- (臨床応用の進歩と展望 : 抗体療法)

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日本臨床 70(12), 2172-2176, 2012-12
NAID 40019493474

The rapid efficacy of abatacept in a patient with rheumatoid vasculitis

FUJII Wataru,KOHNO Masataka,ISHINO Hidetaka,NAKABAYASHI Amane,FUJIOKA Kazuki,KIDA Takashi,NAGAHARA Hidetake,MURAKAMI Ken,NAKAMURA Kaoru,SENO Takahiro,YAMAMOTO Aihiro,KAWAHITO Yutaka
Modern rheumatology 22(4), 630-634, 2012-08-01
NAID 10031027398

Related Pictures

CTLA4 CTLA4-Ig – Beyond the Dish Ctla4 Anti-PD-1 | GRACE :: Lung Cancer antitumor immunity by blocking CTLA4 Antigens, CD80; B-Cell Activation Antigen Figure 2: CTLA-4 may be a core mechanism Figure 1 : T-cell regulation by CD28 and

★リンクテーブル★

リンク元	「CTLA-4」
関連記事	「CTL」

「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 to plasma membrane; • external side of plasma membrane; • clathrin-coated endocytic vesicle; • perinuclear region of cytoplasm;
Biological process	• immune response; • response to DNA damage stimulus; • negative regulation of B cell proliferation; • T cell costimulation; • positive regulation of apoptotic process; • negative regulation of regulatory T cell differentiation; • 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。

「CTL」

　　[★] 細胞傷害性Tリンパ球

[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.

[pmid11583591-17] 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.

[pmid9200449-18] 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.

[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.

[pmid11279502-20] 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.

[pmid11994459-21] 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. PMID 11994459.

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CTLA4