1. Antigen presenting cells and antigen presentation

2. Contents
Antigen presenting cells
Antigen presentation

3. Antigen presenting cell, APC
A variety of cell types which carry antigen in a form that can stimulate lymphocytes. It is also termed accessory cell. professional APC:MΦ,DC,B non-professional APC

4. APCs fall into two categories: professional or non-professional.
To help distinguish between the two types of APCs, those that express MHC class II molecules are often called professional antigen-presenting cells. These professional APCs are very efficient at internalizing antigen.
A non-professional APC does not constitutively express the Major histocompatibility complex proteins required for interaction with naive T cells; these are expressed only upon stimulation of the non-professional APC by certain cytokines such as IFN-γ.

5. The 3 types of professional APCs
there are 3 main types of professional APCs
At certain development stages they grow branched projections, the dendrites, that give the cell its name
Constitutively express a high level of MHC II and the co-stimulatory protein,B7. the most effective APC
must be activated by the process of phagocytosis before expressing class II MHC and B7.
Constitutively express class II MHC but must be activated to produce B7.

6. I. Dendritic cells (DC)
Dendritic cells were first described by Paul Langerhans (Langerhans cells) in the late nineteenth century. It wasn't until 1973, however, that the term "dendritic cells" was coined by Ralph M. Steinman and Zanvil A. Cohn. In 2007 Steinman was awarded the Albert Lasker Award for Basic Medical Research for his discovery.

7. Marks Mouse 33D1,NLDC145 Rat OX62 Human CD1a,CD11c,CD83
Other marks:MHCⅡ,CD80,CD86

8. Sources of DC HSC Myeloid progenitor Lymphoid progenitor DC Mo PMN DC
GM-CSF
TNF-a
IL-4
HSC
Myeloid progenitor
Lymphoid progenitor DC Mo
PMN DC DC
macrophage

9. Dendritic Cell Maturation
                                                                                                                                                             
LPS
IL-1,TNFα

10. B
Menu F

11. Functions of DC: antigen presentation, immune activation, immune tolerance
                                                                                                                                                                          
DC通过FcR和C3bR吞噬被抗体和补体包被的抗原；通过甘露糖受体吞噬甘露糖化的抗原，受体介导的内吞句有选择性、高效性和饱和性。
DC非特异性吞噬颗粒抗原能力很弱。
FDC表面捕获抗原，无吞噬处理功能，直接提呈给B细胞识别

12. Antigen presenting cells
mononuclear phagocyte system, MPS
1.Differentiation and distribution
2. Surface markers
3. function

13. Differentiation and distribution of MPS
Bone marrow
Blood
tissues
HSC
monocyte
macrophage
Myeloid progenitor
Pre-monocyte
monocyte

14. Mononuclear phagocyte system, MPS
1. Surface markers:
MHC-I/Ⅱmolecules
CKR: M-CSFR
CAM: LFA-1,ICAM-1,B7,CD40
FcR, CR1/3/4
2. secretion：
-enzymes: lysosome , myeloperoxidase
-cytokines (IL-1,TNF,IL-12)
-complement:C1～C9, Bf
-coagulation factor, PG, LTs, ACTH, etc.
分泌功能：
-产生溶酶体酶、髓过氧化物酶、活性氧等，与杀伤和抗原处理有关
-分泌细胞因子、补体、凝血因子等，与炎症反应有关；
-产生前列腺素、白三烯、ACTH、内啡肽等，与免疫调节有关。

15. Biological functions of MPS
Phagocytosis
antitumor：indirect or direct killing, ADCC;
participating in immune response：
-Ag presenting, providing the second signal；
-CMI
participating in immune regulation:
-positive regulation：secrete IL-1/12，TNF-α
-negative regulation：PG, TGF-β
Mediating inflammation: phagocytosis, secrete inflammation medium
促炎细胞因子：TNF-alpha, IL-1, IL-6, IL-8, 参与局部和全身的炎症反应。

16. phagocytosis

17. Antigen presenting cells
B cells
BCR摄取抗原，在抗原浓度低的情况下，有效摄入和递呈，显示浓缩抗原效应。主要摄取可溶性抗原。

18. The properties of various APCs

19. Ag presentation Definition APC Ag presentation
-MHC class I molecule pathway
-MHC class II molecule pathway

20. Antigen capturing Phagocytosis Pinocytosis
Receptor-mediated endocytosis

21. Antigen processing
The conversion of an antigen into a form in which it can be recognized by lymphocytes.

22. Antigen presentation
The process by which certain cells in the body (APC) express antigen peptide-MHC molecule complex on their cell surface in a form recognize by lymphocytes.

23. Recourses of antigens * exogenous antigen * endogenous antigen
递呈抗原的来源与抗原处理和递呈途径及诱导的免役应答类型密切相关。

24. The site of pathogen replication or mechanism of antigen uptake determines the antigen processing pathway used
EXTRACELLULAR OR
ENDOSOMAL REPLICATION Y Y
Vesicular Compartment
Contiguous with extracellular fluid
Exogenous processing
(Streptococcal, Mycobacterial antigens)
INTRACELLULAR REPLICATION
The intracellular replication takes place in cytosolic compartment and these pathogens are processed by endogenous processing pathway. The pathogens are for example viral antigens.The tumor antigens also use this pathway for processing..
extracellular replication or endosomal replication take place in extracellular fluid or intracellular vesicles. These infectious agents can be processed by exogenous processing pathway. For example streptococcal bacteria replicate in extracellular fluid and are taken up by phagocytosis. The mycobacteria replicate in vesicular compartment, such as endosome or lysosome and they are processed by exogenous processing pathway. The immune system has different strategies for eliminating pathogens from these two sites. Cells infected with viruses or with bacteria that live in the cytosol are eliminated by cytotoxic T cells; Pathogens and their products in the vesicular compartments of cells are detected by a different class of CD4 T cell.
Cytosolic compartment
Endogenous processing
(Viral antigens)
Distinct mechanisms of antigen generation are used to raise
T cells suited to the elimination of endogenous or exogenous pathogens

25. Pathogens in Cytosol/Vesicles

26. The pathway of MHC I -associated endogenous Ag presentation
endogenous antigen（such as virus Ag, tumor Ag)
cytoplasm degraded by proteasome
antigen peptide（8-13 AA）
　 transported to endoplasmic reticulum by TAP
Peptide/MHC-I molecule complex
to surface of APC
submit to CD8+T

27. Degradation in the proteasome
Cytoplasmic cellular proteins, including non-self proteins
are degraded continuously by a multicatalytic protease of 28 subunits
Proteins in cells are continually being degraded and replaced with newly synthesized proteins. Much cytosolic protein degradation is carried out by a large, multicatalytic protease complex called the proteasome. The proteasome is a large cylindrical complex of some 28 subunits. Proteins to be degraded are introduced into the core of the proteasome and are there broken down into short peptides. Two subunits of the proteasome, called LMP2 and LMP7, are encoded within the MHC near the TAP1 and TAP2 genes. A third subunit, MECL-1, which is not encoded within the MHC, is also induced by interferons and also displaces a constitutive proteasome subunit. These three inducible subunits and their constitutive counterparts are thought to be the active proteases of the proteasome.
LMP: low molecule peptide
MECL-1:
内源性蛋白通过蛋白酶体的孔道，被降解为6-30aa
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

28. 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.

29. 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: 钙联蛋白
calreliculin ：钙网蛋白
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

30. B
Menu F

31. B
Menu F

32. The pathway of MHC II -associated exogenous Ag presentation
Exogenous antigen newly synthesised MHC class II molecule
（in the endoplasmic reticulum ）
early endosome li binds in the groove of MHC class II molecule
lysosome protease MIIC
late endosome li degrade
protease
Degrade into 1318AA peptide MHC class II molecule
Ag peptide/MHC class II molecule complex
transport to the surface of APC, recognized by CD4+T
Phagocytosis, pinocytosis,
FcR-phagocytosis
新合成的MHCII在内质网与li结合, li为三聚体,每一个亚单位与一个分子的MHCII抗原结合槽结合,形成九链聚合体.其功能有两个: (1) 防止无关肽与MHCII结合; (2) 引导MHCII离开内质网, 运至含有特异性肽的内体. 当MHCII小泡与内体融合, 酸性环境下,蛋白酶将li降解, 仅留CLIP(class II -associated invariant-chain peptide，II类相关恒定链肽)仍结合在抗原结合槽内. HLA-DM可促进CLIP从抗原槽内解离, 并促进抗原肽结合进去。

33. Uptake of exogenous antigens
Membrane Ig
receptor mediated
uptake Y Y
Phagocytosis
Complement receptor
mediated phagocytosis Y
Pinocytosis
巨噬细胞：吞噬、胞饮和受体介导的胞吞作用。
树突状细胞：以胞饮和受体介导的胞吞作用为主，
B细胞：以BCR特异性摄取抗原为主；非特异性胞饮为辅。
opsonization Y
Fc receptor mediated phagocytosis

34. Exogenous pathway Protein antigens Uptake In endosome Endosomes
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

35. The functions of Ii: CLIP：class II-associated invariant chain peptide
involve in the assembling and folding of MHC class
II molecule;
Block the groove of MHC class II molecule;
Lead the assembled class II molecule to MⅡC.
CLIP:II类相关恒定链肽段
CLIP：class II-associated invariant chain peptide

36. B
Menu F

37. B
Menu F

38. Cross-presentation
Class I MHC molecules present exogenous Ags to CD8+ T cells
Cross-presentation of Ags by DC plays an important role in anti-viral infection and anti-tumor immunity.
Refers to the presentation of exogenous antigens on MHC class I molecules.
This pathway is thought to play an important role in activating CD8 T cells to respond to virus-infected cells and to some tumors.