出典(authority):フリー百科事典『ウィキペディア(Wikipedia)』「2014/11/14 21:31:01」(JST)
MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other being MHC class II) and are found on nearly every nucleated cell of the body. Their function is to display fragments of proteins from within the cell to T cells; healthy cells will be ignored, while cells containing foreign proteins will be attacked by the immune system. Because MHC class I molecules present peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called the cytosolic or endogenous pathway.[1]
Class I MHC molecules bind peptides generated mainly from degradation of cytosolic proteins by the proteasome. The MHC I:peptide complex is then inserted into the plasma membrane of the cell. The peptide is bound to the extracellular part of the class I MHC molecule. Thus, the function of the class I MHC is to display intracellular proteins to cytotoxic T cells (CTLs). However, class I MHC can also present peptides generated from exogenous proteins, in a process known as cross-presentation.
A normal cell will display peptides from normal cellular protein turnover on its class I MHC, and CTLs will not be activated in response to them due to central and peripheral tolerance mechanisms. When a cell expresses foreign proteins, such as after viral infection, a fraction of the class I MHC will display these peptides on the cell surface. Consequently, CTLs specific for the MHC:peptide complex will recognize and kill the presenting cell.
Alternatively, class I MHC itself can serve as an inhibitory ligand for natural killer cells (NKs). Reduction in the normal levels of surface class I MHC, a mechanism employed by some viruses during immune evasion or in certain tumors, will activate NK cell killing.
MHC class I molecules consist of two polypeptide chains, α and β2-microglobulin (b2m). The two chains are linked noncovalently via interaction of b2m and the α3 domain. Only the α chain is polymorphic and encoded by a HLA gene, while the b2m subunit is not polymorphic and encoded by the Beta-2 microglobulin gene. The α3 domain is plasma membrane-spanning and interacts with the CD8 co-receptor of T-cells. The α1 and α2 domains fold to make up a groove for peptides to bind. MHC class I molecules bind peptides that are 8-10 amino acid in length (Parham 87).
The peptides are generated mainly in the cytosol by the proteasome. The proteasome is a macromolecule that consists of 28 subunits, of which half affect proteolytic activity. The proteasome degrades intracellular proteins into small peptides that are then released into the cytosol. The peptides have to be translocated from the cytosol into the endoplasmic reticulum (ER) to meet the MHC class I molecule, whose peptide-binding site is in the lumen of the ER. They have membrane proximal Ig fold.
The peptide translocation from the cytosol into the lumen of the ER is accomplished by the transporter associated with antigen processing (TAP). TAP is a member of the ABC transporter family and is a heterodimeric multimembrane-spanning polypeptide consisting of TAP1 and TAP2. The two subunits form a peptide binding site and two ATP binding sites that face the cytosol. TAP binds peptides on the cytoplasmic side and translocates them under ATP consumption into the lumen of the ER. The MHC class I molecule is then, in turn, loaded with peptides in the lumen of the ER.
The peptide-loading process involves several other molecules that form a large multimeric complex consisting of TAP, tapasin, calreticulin, calnexin, and Erp57. Calnexin acts to stabilize the class I MHC α chains prior to β2m binding. Following complete assembly of the MHC molecule, calnexin dissociates. The MHC molecule lacking a bound peptide is inherently unstable and requires the binding of the chaperones calreticulin and Erp57. Additionally, tapasin binds to the MHC molecule and serves to link it to the TAP proteins, thus facilitating enhanced peptide loading and colocalization.
Once the peptide is loaded onto the MHC class I molecule, the complex dissociates and it leaves the ER through the secretory pathway to reach the cell surface. The transport of the MHC class I molecules through the secretory pathway involves several posttranslational modifications of the MHC molecule. Some of the posttranslational modifications occur in the ER and involve change to the N-glycan regions of the protein, followed by extensive changes to the N-glycans in the Golgi apparatus. The N-glycans mature fully before they reach the cell surface.
Peptides that fail to bind MHC class I molecules in the lumen of the endoplasmic reticulum (ER) are removed from the ER via the sec61 channel into the cytosol,[2][3] where they might undergo further trimming in size, and might be translocated by TAP back into ER for binding to an MHC class I molecule.
For example, an interaction of sec61 with bovine albumin has been observed.[4]
MHC class I molecules are loaded with peptides generated from the degradation of ubiquitinated cytosolic proteins in proteasomes. As viruses induce cellular expression of viral proteins, some of these products are tagged for degradation, with the resulting peptide fragments entering the endoplasmic reticulum and binding to MHC I molecules. It is in this way, the MHC class I-dependent pathway of antigen presentation, that the virus infected cells signal T-cells that abnormal proteins are being produced as a result of infection.
The fate of the virus-infected cell is almost always induction of apoptosis through cell-mediated immunity, reducing the risk of infecting neighboring cells. As an evolutionary response to this method of immune surveillance, many viruses are able to down-regulate or otherwise prevent the presentation of MHC class I molecules on the cell surface. In contrast to cytotoxic T lymphocytes, Natural killer (NK) cells are normally inactivated upon recognizing MHC I molecules on the surface of cells. Therefore, in the absence of MHC I molecules, NK cells are activated and recognize the cell as aberrant, suggesting they may be infected by viruses attempting to evade immune destruction. Several human cancers also show down-regulation of MHC I, giving transformed cells the same survival advantage of being able to avoid normal immune surveillance designed to destroy any infected or transformed cells.[5]
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リンク元 | 「主要組織適合複合体」「インターフェロン」「キラーT細胞」 |
拡張検索 | 「MHC class II」「MHC class II gene」 |
関連記事 | 「class」「I」「MHC class」「MH」「Id」 |
MHC class I | *MHC class II | |
MHC発現組織 | 全ての有核細胞(×赤血球) | CD4陽性T細胞 |
CD8陽性T細胞 | ||
抗原提示細胞(マクロファージ、樹状細胞、 | ||
抗原認識するリンパ球 | Tc細胞 | Th細胞 |
ドメイン構造 | α鎖(α1,2,3を持つ分子)とβ2-microgloblin | α鎖(α1,α2を持つ分子)とβ鎖(β1,β2を持つ分子) |
遺伝子座 | HLA-A,B,C, | HLA-DP,DQ,DR |
提示されるペプチド | 内在抗原 | 外来抗原 |
抗原ペプチドの長さ | 9残基 | 12-30残基 |
抗原ペプチドとMHCとの相互作用部位 | 2残基 | 3(免疫学授業プリント)
4(IMM.131) |
MHC class I | MHC class II | ||
リンパ組織 | T細胞 | +++ | + |
B細胞 | +++ | +++ | |
マクロファージ | +++ | ++ | |
樹状細胞 | +++ | +++ | |
胸腺上皮細胞 | + | +++ | |
有核細胞 | 好中球 | +++ | - |
肝細胞 | + | - | |
腎臓 | + | - | |
脳 | + | - | |
無核細胞 | 赤血球 | - | - |
主要組織適合遺伝子複合体 移植抗原として発見された抗原系 応答免疫(抗原提示)に関与する ヒト(HLA complex) human leucocyte antigen HLA ドメイン構造 クラスI A B C クラスII DP DQ DR 多型性がある 12種類のHLAを発現(父由来、母由来) マウス(H2 complex) Histcompatibility-2 ドメイン構造 クラスI K D クラスII A E MHCの歴史 G.Snell マウスH2が移植の正否を左右する J.Dausset HLAが抗原 B.Benaceraf MHC遺伝子を明らかにし、MHCが免疫応答に関与していることを証明
クラスI H鎖 β2-microglobulin クラスII α鎖 β鎖 細胞外領域 膜貫通領域 細胞内領域 ドメイン Igスーパーファミリー クリスタログラフィー crystallography
抗原処理 抗原提示 クラスI (proteasome TAP) クラスI抗原提示(内在性抗原) ①ほとんどの細胞が提示 ただし赤血球には発現していない ②細胞内:内在抗原をプロテアソーム(LMP複合体)が分子切断→ERに移動 ③ERI TAPトランスポーターによりER内に移動 クラスI+ペプチド複合体形成 ④細胞表面に移動 ⑤Tc(CD8+ T細胞)細胞が認識:標的細胞を障害 クラスII (Ii=invariant chain, HLA-DM) クラスII抗原提示(外来抗原) ①抗原提示細胞:貪食、飲食による取り込み ②ファゴリソゾーム:ペプチドに分解 ③小胞体(ER):(MHC class II + Ii鎖)複合 ④ファゴリソゾーム:HLA-DMがIi鎖を解離 ペプチドを提示→(MHC class II + ペプチド)複合体 ⑤細胞表面に移動 ⑥Th(CD4+T)細胞が認識
最近、E,F,Gが発見された→E,FはT細胞、Gは胎盤トロホブラストが発現(妊娠免疫に重要)
サイトカイン:TNPet,C, 酵素:21-hydroxylase クラス(領域 亜領域) 遺伝的多塑性 polymorphism 対立遺伝子頻度
-MHC
産生細胞 | 種類 | 誘発因子 | 作用 | ||
I型インターフェロン | IFN-α | 好中球、マクロファージなど | 14種類以上 | ウイルス、細菌内毒素 | 抗ウイルス効果、抗腫瘍効果 |
IFN-β | 線維芽細胞、上皮細胞など | 1種類 | ウイルス、2本鎖RNA | 抗ウイルス効果、抗腫瘍効果 | |
II型インターフェロン | IFN-γ | T細胞、NK細胞など | 1種類 | 抗原刺激、サイトカイン | 免疫細胞の活性化、免疫系の制御 |
発熱 | ほぼ必発 |
甲状腺機能異常 | 約10% |
間質性肺炎 | 非常に稀 |
精神症状 | 約10% |
白血球減少 | ほぼ必発 |
血小板減少 | ほぼ必発 |
蛋白尿 | 約10% |
糖尿病 | 0.1-5% |
口腔内病変 | 約20% |
脱毛 | 約5% |
眼底出血 | 約20% |
-細胞傷害性T細胞
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