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第十一章 抗原的加工与递呈.

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Presentation on theme: "第十一章 抗原的加工与递呈."— Presentation transcript:

1 第十一章 抗原的加工与递呈

2 T cells do not recognise native antigens
Y B Y B Y B Y B Y B Y B Y B Y B Y B Y Y Y Y Y Y BCR交联 活化增殖、产生抗体 Y T Y T 无增殖 无CK产生

3 Antigens must be processed in order to be recognised by T cells
Soluble native Ag Cell surface native Ag Soluble peptides of Ag Cell surface peptides of Ag 抗原肽-MHC复合物 抗原加工、递呈 无应答 无应答 无应答 无应答 T cell response

4 基本内容 基本概念 抗原递呈细胞的种类 抗原加工和递呈的途径 抗原加工递呈的生理意义

5 一、基本概念 抗原加工:蛋白质抗原在细胞内被降解成能与MHC分子结合的肽的过程。
抗原递呈:MHC分子与抗原肽结合,将其展示于细胞表面供T细胞识别的过程。 内源性抗原:细胞内产生的蛋白质抗原,包括自身抗原和非己抗原----MHCⅠ分子递呈。 外源性抗原:由细胞外摄入细胞内的蛋白质抗原,包括非己抗原和自身抗原---MHCⅡ分子递呈。

6 二、抗原递呈细胞的种类 APC:即抗原递呈细胞,表达MHC和协同刺激分子,能够摄取、加工、处理抗原,并把抗原肽递呈给T细胞的一类特化的细胞群,包括DC、巨噬细胞、活化的B细胞和其他非专职APC。

7 APC的分类: 非专职APC:内皮细胞、上皮细胞、纤维母细胞及脑内小胶质细胞等。 专职APC:DC、巨噬细胞、活化的B细胞

8 1. 树突状细胞(dendritic cell, DC)
由美国学者Steinman于1973年发现,因其伸出树枝样突起而得名。1993年Inaba等用GM-CSF体外扩增获得成功。 根据来源:分为髓系来源的DC和淋巴系来源的DC。 根据分布:淋巴组织中的DC(并指状DC,边缘区DC);非淋巴样组织中的DC(间质性DC、郎格罕斯细胞);体液中的DC(隐蔽细胞,血液DC)

9 Fig2-4 Mature DC suspended in media by colony( ×400)

10 图2-5 呈散在生长的成熟DC( ×400) Fig2-5 scattered mature DC( ×400)

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12 DC的特点及功能: 通过形态学、组合性表面标志及在混合淋巴细胞反应中能够刺激初始T细胞增殖鉴定。
人DC的主要特征性标志为CD11c、CD1a、CD83,是惟一能激活初始T细胞的APC。 是目前所知的机体内功能最强的APC,其抗原递呈功能是巨噬细胞的10-100倍。 通过三种方式摄取抗原:巨吞饮、受体介导的内吞作用、吞噬作用。

13 未成熟DC与成熟DC的区别: 摄取抗原的能力降低。 抗原加工、递呈功能增强。
MHC、协同刺激分子(CD80、CD86)、黏附分子(LFA-1、ICAM-1)表达上调。 刺激T细胞增殖的能力增强。

14 2. 巨噬细胞(macrophage, MФ) 由血液中的单核细胞分化而来。 具有强大的吞噬功能(大吞噬细胞)。 可通过三种方式摄取抗原。
不能活化未致敏T细胞。 静止状态几乎不表达 MHC和协同刺激分子。

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20 3. B细胞 主要加工和递呈可溶性抗原。 通过两种方式摄取抗原:胞饮、受体介导 通过BCR高效摄取抗原,具有浓集抗原的作用。
组成性表达MHCII类分子,但不表达协同刺激分子。

21 三、抗原加工和递呈的途径 经典途径: MHCⅠ类分子递呈内源性Ag----CD8+T MHCⅡ类分子递呈外源性Ag------CD4+T
非经典途径-----交叉致敏

22 (一)外源性抗原的加工递呈 又称为MHCⅡ类途径。 分为抗原的摄取、加工、 MHCⅡ类分子的合成与转运、MHCⅡ类分子荷肽、递呈几个阶段。

23 1. 外源性抗原的摄取 通过胞吞外源性抗原由细胞外进入细胞内,形成内体。 内体:胞吞的抗原被质膜包围形成的空泡,是外源性抗原加工的场所。
内体经历早期、中期、晚期内体几个阶段,逐渐成熟,最终与溶酶体融合。

24 2. 外源性抗原的加工 外源性抗原在内体的酸性环境和各种组织蛋白酶的作用下被降解成适于与MHCⅡ类分子结合的肽。

25 3. MHC Ⅱ类分子的生物合成和转运 合成场所:粗面内质网 α/β二聚体与Ii链结合,形成Ii3α3β3
Ii链:Ia分子相关的不变链(Ia-associated invariant chain, Ii链) CLIP:Ii链中81-104位氨基酸残基的特殊肽段结构,能与所有MHCⅡ类分子的抗原结合槽以不同亲和力结合,称为Ⅱ类分子结合的不变肽链(class II associated invariant peptide, CLIP)

26 Ii链的作用: 帮助II类分子折叠和装配 阻止II类分子与ER中新合成的肽或内源性抗原肽结合 引导II类分子进入内体

27 4. MHCⅡ类分子荷肽 荷肽:MHC分子与抗原肽结合的过程, 在M Ⅱ C和C ⅡV中进行。
M Ⅱ C和C ⅡV: M Ⅱ C即MHC Ⅱ 类区室(MHC class Ⅱ compartment),C ⅡV即含MHCⅡ类分子的空泡(MHC class Ⅱ-cintaining vesicles),是富含外源性抗原肽和HLA-DM分子的内体。

28 MHCⅡ类分子荷肽过程: (1)蛋白水解酶降解Ii链,CLIP与II类分子结合。 (2)HLA-DM分子与HLAII-CLIP复合物结合。

29 5. 外源性抗原的递呈 通过胞吐作用,空泡膜与细胞膜融合,外源性抗原肽-II类分子表达于APC表面,供CD4+T细胞识别。

30 Uptake of exogenous antigens
Membrane Ig receptor mediated uptake Y Y Phagocytosis Complement receptor mediated phagocytosis Y Pinocytosis Y Fc receptor mediated phagocytosis Uptake mechanisms direct antigen into intracellular vesicles for exogenous antigen processing

31 Receptor-mediated uptake enhances the
efficiency of the T cell response Non-receptor -mediated uptake Receptor-mediated antigen uptake 100 50 75 25 % of max. T cell response 10-1 10-2 10-3 Antigen gml-1

32 Exogenous pathway Cell surface Protein antigens Uptake In endosome
Increase in acidity Protein antigens In endosome Endosomes To lysosomes Cathepsin B, D and L proteases are activated by the decrease in pH Proteases produce ~24 amino acid long peptides from antigens Drugs that raise the pH of endosomes inhibit antigen processing

33 Activation of Cathepsin B at low pH
Loss of the pro-region exposes the catalytic site of the protease At higher pH cathepsin B exists in a pro-enzyme form Acidification of the endosome alters the conformation of the proenzyme to allow cleavage of the pro-region Hence: drugs that alter acidification of the endosomes disturb exogenous antigen processing

34 MHC class II maturation and invariant chain
In the endoplasmic reticulum Invariant chain stabilises MHC class II by non- covalently binding to the immature MHC class II molecule and forming a nonomeric complex Need to prevent newly synthesised, unfolded self proteins from binding to immature MHC

35 Invariant chain structure
Three extended peptides each bind into the grooves of three MHC class II molecules to form the nonomeric complex

36 Invariant chain CLIP peptide
and b chains of MHC class II molecules CLIP A peptide of the invariant chain blocks the MHC molecule binding site. This peptide is called the CLass II associated Invariant chain Peptide (CLIP)

37 Class II associated invariant chain peptide (CLIP)
Cell surface Uptake Endosomes (inv)3 complexes directed towards endosomes by invariant chain Cathepsin L degrades Invariant chain CLIP blocks groove in MHC molecule MHC Class II containing vesicles fuse with antigen

38 Removal of CLIP ? How can the peptide stably bind to a floppy binding site? Competition between large number of peptides

39 HLA-DM assists in the removal of CLIP
HLA-DR HLA-DM: Crystallised without a peptide in the groove In space filling models the groove is very small

40 HLA-DM HLA-DR Single pocket in “groove” insufficient to accommodate
a peptide HLA-DR Multiple pockets in groove sufficient to accommodate a peptide

41 HLA-DM catalyses the removal of CLIP
Replaces CLIP with a peptide antigen using a catalytic mechanism (i.e. efficient at sub-stoichiometric levels) Discovered using mutant cell lines that failed to present antigen HLA-DO may also play a role in peptide exchange MIIC compartment Sequence in cytoplasmic tail retains HLA-DM in endosomes HLA-DM HLA-DR

42 Surface expression of MHC class II-
peptide complexes Exported to the cell surface (t1/2 = 50hr) Sent to lysosomes for degradation MIIC compartment sorts peptide-MHC complexes for surface expression or lysosomal degradation

43 (二)内源性抗原的加工递呈 又称为MHCⅠ类途径。 分为内源性抗原的加工、转运、MHCⅠ类类分子荷肽、递呈几个阶段。

44 1. 内源性抗原的加工 蛋白酶体:一种存在于大多数细胞内的大分子多重蛋白酶复合体
蛋白酶体将胞内蛋白质降解,在LMP2和LMP7的作用下产生6-10个氨基酸残基的肽。

45 2. 内源性抗原肽的转运 由TAP选择性的将8-15个氨基酸残基的肽转运到内质网。

46 3. MHCⅠ类分子荷肽 在内质网中进行 在钙联蛋白、钙网蛋白的协助下折叠形成α/β2m二聚体,通过TAP1相关蛋白的作用结合于内质网孔道的内侧口,并与内源性抗原肽结合。

47 4. 内源性抗原肽的递呈 结合了肽的I类分子在高尔基体中与TAP1相关蛋白解离,通过外吐空泡运送到细胞表面,供CD8+T细胞识别。

48 Degradation in the proteasome
Cytoplasmic cellular proteins, including non-self proteins are degraded continuously by a multicatalytic protease of 28 subunits The components of the proteasome include MECL-1, LMP2, LMP7 These components are induced by IFN- and replace constitutive components to confer proteolytic properties. LMP2 & 7 encoded in the MHC Proteasome cleaves proteins after hydrophobic and basic amino acids and releases peptides into the cytoplasm

49 Crystal Structure Of The 20s Proteasome
From Yeast View End on

50 ENDOPLASMIC RETICULUM
Peptide antigens produced in the cytoplasm are physically separated from newly formed MHC class I ENDOPLASMIC RETICULUM Newly synthesised MHC class I molecules Peptides need access to the ER in order to be loaded onto MHC class I molecules CYTOSOL

51 Transporters associated with antigen processing (TAP1 & 2)
ER membrane Lumen of ER Cytosol ER membrane Lumen of ER Cytosol ATP-binding cassette (ABC) domain Hydrophobic transmembrane domain Peptide antigens from proteasome TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide Transporter has preference for >8 amino acid peptides with hydrophobic C termini.

52 Maturation and loading of MHC class I
Endoplasmic reticulum TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide Calnexin binds to nascent class I chain until 2-M binds B2-M binds and stabilises floppy MHC Tapasin, calreticulin, TAP 1 & 2 form a complex with the floppy MHC Cytoplasmic peptides are loaded onto the MHC molecule and the structure becomes compact

53 Fate of MHC class I Exported to the cell surface
Sent to lysosomes for degradation

54 Evasion of immunity by interference with endogenous antigen processing
Endoplasmic reticulum Sent to lysosomes for degradation TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 Peptide TAP-1 TAP-2 HSV protein blocks transport of viral peptides into ER

55 (三)非经典递呈途径----交叉递呈 MHCI类分子也能递呈外源性抗原,MHCII类分子也能递呈内源性抗原。 不是抗原递呈的主要方式。

56 四、抗原加工递呈的意义 实现免疫系统对非己抗原的免疫监视作用 免疫调节作用

57 小 结 基本概念:APC APC的种类 内外性抗原加工递呈的过程 生理意义


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