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

PrepTutorEJDIC

1. certificate of deposit / (また『C.D.』)Civil Defense民間防衛

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/12/14 12:55:23」(JST)

wiki en

[Wiki en表示]

CD28 molecule
Structure of human CD28.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1YJD
Identifiers
Symbols	CD28; Tp44
External IDs	OMIM: 186760 MGI: 88327 HomoloGene: 4473 ChEMBL: 5191 GeneCards: CD28 Gene
Gene Ontology Molecular function • protease binding • SH3/SH2 adaptor activity • protein binding • coreceptor activity • identical protein binding Cellular component • cytosol • plasma membrane • integral to plasma membrane • external side of plasma membrane Biological process • humoral immune response • cell surface receptor signaling pathway • viral reproduction • T cell costimulation • cytokine biosynthetic process • positive regulation of T cell proliferation • regulatory T cell differentiation • positive regulation of viral genome replication • positive regulation of interleukin-2 biosynthetic process • positive regulation of translation • positive regulation of anti-apoptosis • positive regulation of mitosis • regulation of defense response to virus by virus Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	940	12487
Ensembl	ENSG00000178562	ENSMUSG00000026012
UniProt	P10747	P31041
RefSeq (mRNA)	NM_001243077.1	NM_007642.4
RefSeq (protein)	NP_001230006.1	NP_031668.3
Location (UCSC)	Chr 2: 204.57 – 204.6 Mb	Chr 1: 60.72 – 60.77 Mb
PubMed search	[1]	[2]

CD28 (Cluster of Differentiation 28) is one of the molecules expressed on T cells that provide co-stimulatory signals, which are required for T cell activation. CD28 is the receptor for CD80 (B7.1) and CD86 (B7.2). When activated by Toll-like receptor ligands, the CD80 expression is upregulated in antigen presenting cells (APCs). The CD86 expression on antigen presenting cells is constitutive. CD28 is the only B7 receptor constitutively expressed on naive T cells.

Stimulation through CD28 in addition to the T Cell Receptor (TCR) can provide a potent co-stimulatory signal to T cells for the production of various interleukins (IL-2 and IL-6 in particular). Association of the TCR of a naive T cell with MHC:antigen complex without CD28:B7 interaction results in a T cell that is anergic.

Signalling

CD28 possesses an intracellular domain with several residues that are critical for its effective signalling. The YMNM motif beginning at tyrosine 170 in particular is critical for the recruitment of SH2-domain containing proteins, especially PI3K, Grb2 and Gads. The Y170 residue is important for the induction of Bcl-XL via mTOR and enhancement of IL-2 transcription via PKCθ, but has no effect on proliferation and results a slight reduction in IL-2 production. The N172 residue (as part of the YMNM) is important for the binding of Grb2 and Gads and seems to be able to induce IL-2 mRNA stability but not NF-κB translocation. The induction of NF-κB seems to be much more dependent on the binding of Gads to both the YMNM and the two proline-rich motifs within the molecule. However, mutation of the final amino acid of the motif, M173, which is unable to bind PI3K but is able to bind Grb2 and Gads, gives little NF-κB or IL-2, suggesting that those Grb2 and Gads are unable to compensate for the loss of PI3K . IL-2 transcription appears to have two stages; a Y170-dependent, PI3K-dependent initial phase which allows transcription and a second phase which is dependent on formation of an immune synapse and PI3K-independent which results in enhancement of IL-2 mRNA stability. Both are required for full production of IL-2.

CD28 also contains two proline-rich motifs that are able to bind SH3-containing proteins. Itk and Tec are able to bind to the N-terminal of these two motifs which immediately succeeds the Y170 YMNM; Lck binds the C-terminal. Both Itk and Lck are able to phosphorylate the tyrosine residues which then allow binding of SH2 containing proteins to CD28. Binding of Tec to CD28 enhances IL-2 production, dependent on binding of its SH3 and PH domains to CD28 and PIP3 respectively. The C-terminal proline-rich motif in CD28 is important for bringing Lck and lipid rafts into the immune synapse via filamin-A. Mutation of the two prolines within the C-terminal motif results in reduced proliferation and IL-2 production but normal induction of Bcl-XL.

Structure

The first structure of CD28 was obtained in 2005 by the T-cell biology group at the University of Oxford.

CD28 as a drug target

The drug TGN1412, which was produced by the German biotech company TeGenero and which unexpectedly caused multiple organ failure in trials, is a superagonist of CD28. Unfortunately it is often ignored that the same receptors also exist on cells other than lymphocytes. CD28 has also been found to stimulate eosinophil granulocytes where its ligation with anti-CD28 leads to the release of IL-2, IL4, IL-13 and IFN-γ.

Interactions

CD28 has been shown to interact with PIK3R1, Grb2 and GRAP2.

See also

• List of human clusters of differentiation

References

Further reading

• Linsley PS, Ledbetter JA (1993). "The role of the CD28 receptor during T cell responses to antigen". Annu. Rev. Immunol. 11: 191–212. doi:10.1146/annurev.iy.11.040193.001203. PMID 8386518.
• Lenschow DJ, Walunas TL, Bluestone JA (1996). "CD28/B7 system of T cell costimulation". Annu. Rev. Immunol. 14: 233–58. doi:10.1146/annurev.immunol.14.1.233. PMID 8717514.
• Greenfield EA, Nguyen KA, Kuchroo VK (1998). "CD28/B7 costimulation: a review". Crit. Rev. Immunol. 18 (5): 389–418. PMID 9784967.
• Chang TT, Kuchroo VK, Sharpe AH (2002). "Role of the B7-CD28/CTLA-4 pathway in autoimmune disease". Curr. Dir. Autoimmun.. Current Directions in Autoimmunity 5: 113–30. doi:10.1159/000060550. ISBN 3-8055-7308-1. PMID 11826754.
• Bour-Jordan H, Blueston JA (2002). "CD28 function: a balance of costimulatory and regulatory signals". J. Clin. Immunol. 22 (1): 1–7. doi:10.1023/A:1014256417651. PMID 11958588.
• Greenway AL, Holloway G, McPhee DA, et al. (2004). "HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication". J. Biosci. 28 (3): 323–35. doi:10.1007/BF02970151. PMID 12734410.
• Bénichou S, Benmerah A (2003). "[The HIV nef and the Kaposi-sarcoma-associated virus K3/K5 proteins: "parasites"of the endocytosis pathway]". Med Sci (Paris) 19 (1): 100–6. doi:10.1051/medsci/2003191100. PMID 12836198.
• Tolstrup M, Ostergaard L, Laursen AL, et al. (2004). "HIV/SIV escape from immune surveillance: focus on Nef". Curr. HIV Res. 2 (2): 141–51. doi:10.2174/1570162043484924. PMID 15078178.
• Anderson JL, Hope TJ (2005). "HIV accessory proteins and surviving the host cell". Current HIV/AIDS reports 1 (1): 47–53. doi:10.1007/s11904-004-0007-x. PMID 16091223.
• Li L, Li HS, Pauza CD, et al. (2006). "Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions". Cell Res. 15 (11–12): 923–34. doi:10.1038/sj.cr.7290370. PMID 16354571.
• Stove V, Verhasselt B (2006). "Modelling thymic HIV-1 Nef effects". Curr. HIV Res. 4 (1): 57–64. doi:10.2174/157016206775197583. PMID 16454711.

External links

• Mouse CD Antigen Chart
• Human CD Antigen Chart

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. 関節リウマチのT細胞標的療法 t cell targeted therapies for rheumatoid arthritis
• 2. BおよびTリンパ球の正常な発生 normal b and t lymphocyte development
• 3. 抗原提示細胞 antigen presenting cells
• 4. リウマチ性疾患を有する男性における抗炎症剤および免疫抑制剤が性腺機能に及ぼす影響 effects of antiinflammatory and immunosuppressive drugs on gonadal function in men with rheumatic diseases
• 5. 肺移植後の免疫抑制の維持 maintenance immunosuppression following lung transplantation

English Journal

• Pitfalls in determining the cytokine profile of human T cells.

• Olsen I, Sollid LM.SourceCentre for Immune Regulation and Department of Immunology, Oslo University Hospital-Rikshospitalet, 0027 Oslo, Norway; Section for Immunology, Norwegian Veterinary Institute, Oslo, Norway. Electronic address: ingrid.olsen@vetinst.no.
• Journal of immunological methods.J Immunol Methods.2013 Apr 30;390(1-2):106-12. doi: 10.1016/j.jim.2013.01.015. Epub 2013 Feb 15.
• Secretion of cytokines by T cells in vitro can be influenced by the methods chosen for T cell activation. However, the awareness of this fact appears insufficient. Two of the most widely applied methods for activation of T cells are phorbol 12-myristate 13-acetate (PMA) together with Ionomycin or an
• PMID 23416458

• Silymarin Inhibits Cell Cycle Progression and mTOR Activity in Activated Human T Cells: Therapeutic Implications for Autoimmune Diseases.

• Gharagozloo M, Javid EN, Rezaei A, Mousavizadeh K.SourceDepartment of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
• Basic & clinical pharmacology & toxicology.Basic Clin Pharmacol Toxicol.2013 Apr;112(4):251-6. doi: 10.1111/bcpt.12032. Epub 2012 Dec 24.
• Silymarin, a complex flavonolignan from the 'milk thistle' (Silybum marianum) plant, exhibits anticarcinogenic, anti-inflammatory and cytoprotective effects. Several reports have demonstrated immunosuppressive activity of silymarin; however, the molecular mechanisms involved in immunomodulatory acti
• PMID 23121838

• Cytotoxic T lymphocyte antigen 4-immunoglobulin G is a potent adjuvant for experimental allergen immunotherapy.

• Maazi H, Shirinbak S, den Boef LE, Fallarino F, Volpi C, Nawijn MC, van Oosterhout AJ.SourceLaboratory of Allergology and Pulmonary Diseases, Department of Pathology and Medical Biology, University Medical Center Groningen (UMCG), GRIAC Research Institute, University of Groningen, Groningen, the Netherlands.
• Clinical and experimental immunology.Clin Exp Immunol.2013 Apr;172(1):113-20. doi: 10.1111/cei.12041.
• Allergen-specific immunotherapy (SIT) is the only treatment for allergic diseases that targets allergen-specific T helper type 2 (Th2) cells, which are the cause of the disease. There is an unmet requirement for adjuvants that increase the clinical efficacy of SIT allowing application of lower doses
• PMID 23480191

Japanese Journal

• 慢性炎症性脱髄性多発神経炎におけるCD28陰性T細胞は病巣への遊走能を有する

• 荒浪 利昌,岡本 智子,山村 隆
• 末梢神経 = Peripheral nerve 22(2), 224-225, 2011-12-01
• NAID 10030408389

• T細胞活性化阻害薬

• 上阪 等
• 日本内科学会雑誌 100(10), 2979-2984, 2011-10-10
• NAID 10030390310

• Characterization of waves of leukocyte recruitment to the lung allograft and

• Taguchi Tsunenori/ Inamura Yukio;/Honma Kiri/ Kimura Daisuke;
• Acta medica Nagasakiensia 56(2), 27-34, 2011-08-00
• MHC-mismatched lung allografts are rapidly rejected by the host immune response. We analyzed cells infiltrating thegrafted lung tissue using a collagenase-digestion method. The grafted lung was filled …
• NAID 110008767588

Related Links

• 抗CD28抗体 | サイトメトリードットコム

CD28抗原（Tp44）は、分子量44kDaの分子がジスルフィド結合したホモダイマーです。CD3 + T細胞の大半に発現します。CD4 + T細胞の方が、CD8 + T細胞より高頻度にCD28抗原を発現しています。CD28抗原は形質細胞及び胸腺細胞にも ...

• T細胞の活性化と抑制｜がん免疫療法｜がん免疫.jp Immuno ...

例）共刺激経路：CD28, CD40, OX40, CD137 など 腫瘍は免疫抑制経路をアップレギュレーションしている可能性があります 5,17。 例）免疫チェックポイント： LAG-3 , CTLA-4, B7-H3 など Focus On: T細胞の活性化と抑制 T細胞阻害と ...

• ヘルパーT細胞 - 脂質と血栓の医学

表1 T細胞と抗原提示細胞の相互作用 T細胞 抗原提示細胞 TCR・CD3・CD4（CD8） MHC＋抗原ペプチド CD2（LFA-2） CD58（マウスではCD48） CD28 CD80（B7-1）、CD86（B7-2） CD152（CTLA-4）

Related Pictures

---

★リンクテーブル★

国試過去問	「114F027」
リンク元	「T細胞」「表面抗原分類」「CTLA-4」「CD25」
拡張検索	「CD8+ CD28- T cell」
関連記事	「CD2」「CD」

「114F027」

　　[★]

• リンパ球の抑制シグナルに関与し、現在、治療標的となっている分子はどれか。2つ選べ。

• a　CD8
• b　CD28
• c　TLR-4(Toll-like receptor-4)
• d　PD-1(programmed cell death-1)
• e　CTLA-4(cytotoxic T lymphocyte-associated molecule-4)

[正答]

DE

※国試ナビ4※　［114F026］←［国試_114］→［114F028］

「T細胞」

　　[★]

英

T cell

同

Tリンパ球、T lymphocyte

関

TCR、B細胞、MHC

• 図：IMM.315(T細胞の成熟)
• 胸腺で成熟したT細胞は血流によって移動し、リンパ節の傍皮質、白脾髄のリンパ性動脈周囲鞘、パイエル板の傍濾胞域に集まる(人間の正常構造と機能 VIIA血管・免疫 p.28)

種類

1. ヘルパーT細胞(Th細胞)
2. キラーT細胞(Tc細胞)
3. サプレッサーT細胞(Treg細胞)

T細胞の抗原認識 (SP.248)

	CD	TCRが抗原と共に認識する分子	認識する細胞
Tc細胞	CD8	MHCクラスI	感染細胞
Th細胞	CD4	MHCクラスII	抗原提示細胞

CD4+ T細胞のサイトカイン放出とその原因

DCが認識する外来異物	DCが分泌する物質	DCに反応する細胞	この細胞が分泌する サイトカイン	NK系の細胞が放出した サイトカインに反応するTh細胞	Th細胞が分泌するサイトカイン
ウイルス、一部の細菌	IL-12	NK細胞(IL-12による)	INF-γ	Th1	IL-2, IFN-γ, TNF-β
原虫など		NKT細胞	IL-4	Th2	IL-4, IL-13, IL-5

Th細胞活性化と接着分子

	抗原提示細胞	Th細胞
主シグナル	MHC classII	TCR, CD3
		CD4
副シグナル	B7{B7-1(CD80)/B7-2(CD86)}	CD28
	VCAM-1(CD106)	VLA-4
	ICAM-1	LFA-1
	LFA-3(CD58)	CD2

「表面抗原分類」

　　[★]

英

cluster of differentiation, CD

• 細胞の表面抗原を認識する抗体を整理した分類

Bリンパ球 CD10,CD19,CD20

Tリンパ球 CD2,CD3,CD5,CD7

幹細胞 CD34

顆粒球 CD13,CD33

単球 CD14：LPSをリガンドとし、Toll-like receptorと共役して細胞内シグナルを伝達する分子。

巨核球 CD41(GpIIb),CD42(GpIb)

NK細胞：CD16(IgGのFc部に対する受容体)、CD56(NCAM-I)

CD1	CD21	CD41	CD61	CD81
CD2	CD22	CD42	CD62	CD82
CD3	CD23	CD43	CD63	CD83
CD4	CD24	CD44	CD64	CD84
CD5	CD25	CD45	CD65	CD85
CD6	CD26	CD46	CD66	CD86
CD7	CD27	CD47	CD67	CD87
CD8	CD28	CD48	CD68	CD88
CD9	CD29	CD49	CD69	CD89
CD10	CD30	CD50	CD70	CD90
CD11	CD31	CD51	CD71	CD91
CD12	CD32	CD52	CD72	CD92
CD13	CD33	CD53	CD73	CD93
CD14	CD34	CD54	CD74	CD94
CD15	CD35	CD55	CD75	CD95
CD16	CD36	CD56	CD76	CD96
CD17	CD37	CD57	CD77	CD97
CD18	CD38	CD58	CD78	CD98
CD19	CD39	CD59	CD79	CD99
CD20	CD40	CD60	CD80	CD100

「CTLA-4」

　　[★]

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。

「CD25」

　　[★]

同

T-cell α-chemoattractant antigen, α-chain of IL-2 receptor

インターロイキン2受容体α鎖 interleukin-2 receptor α-chain、Tac抗原 Tac antigen

関

CD, interleukin-2 receptor

概念

• 親和性の低いIL-2受容体はβ鎖とγ鎖からなりT細胞表面に発現している。MHC class IIと抗原複合体のTCRを介した主シグナルとB7のCD28を介した副シグナルを受けるとT細胞が活性化する。するとT細胞はCD25(α鎖)を発現し、親和性の強いIL-2受容体を形成する。IL-2はT細胞を刺激して増殖や分化を促す。 (IMM.345)

発現細胞

• 活性化したT細胞、B細胞、単球

機能

• IL-2 receptor α chain

「CD8+ CD28- T cell」

　　[★]

同

CD8+ CD28- T cells

同

CD8+ CD28- T cells

「CD2」

　　[★]

同

Leucine-5, SRBC receptor, LFA-2

関

CD

発現細胞

• T細胞、胸腺細胞、NK細胞

分子量

• 45-58

機能

• 接着分子、CD58(LFA-3)に結合。細胞内部でLckに結合し、T細胞を活性化

• リンパ球が抗原提示細胞と相互作用するのに重要 (IMM.343)

別名

• LFA-2, T11

ファミリー

• immunoglobulin

「CD」

　　[★]

• 表面抗原分類 cluster of differentiation
• 膠原病 collagen disease
• 集合管 collecting duct
• クローン病 Crohn's disease