Bloque 4: Antigen presentation Flashcards
Antigen presenting cells, definition
Antigen presenting cells are those cells that express the major histocompatibility complex molecules. Their main function is to display antigens to CD4+ lymphocytes and activate naïve T cells or previously differentiated T cells.
MHC definition and types
Major histocompatibility complex are proteins in the membrane of cells that are recognised by CD4+ and CD8+ T cells.
There are two main classes of MHC molecules:
- MHC I which are present in all nucleated cells and are involved in the presentation of antigens inside the cell. This complex is recognised by CD8+ T cells
- MHC II which is present only in cells specialised on the presentation of antigens. They have to due with extracellular antigens and are recognised by CD4+ T cells
There’s a third class of MHC, MHC-III which has more varied roles in immune response and generally does not involve direct presentation of antigen fragments to T cells.
Dendritic cell properties
Antigen uptake by macropinocytosis and phagocytosis . They can also be useful in viral infections.
MHC expression is low in tissue DCs and high in the ones that are in lymphoid tissues.
Costimulation is constitutive. It is produced by mature nonphagocytic lymphoid dendritic cells and increased with TLR signals, IFN-gamma and CD40-CD40L interactions.
The antigens presented by DCs are peptides, viral antigens and allergens.
DCs are located in lymphoid tissue, connective tissue and epithelia.
Macrophages properties
Antigen uptake by phagocytosis.
The MHC expression is inducible by bacteria and cytokines. Co-stimualtion is also inducible.
Macrophages present particulate antigens, intracellular and extracellular pathogens.
Macrophages are present in lymphoid tissue, connective tissue and body cavities. Macrophage activation leads to cellular immunity.
B cells properties as APCs
The antigen uptake is done by antigen-specific receptors (immunoglobulins)
MHC expression is constitutive, although it increases on activation.
Co-stimulator delivery is inducible.
The antigens presented by B cells are soluble antigens, toxins and viruses.
B cells are located in lymphoid tissue and in peripheral blood. Once B cells activate, humoral immunity takes place.
Functions of APCs
General functions:
- Antigen capture, processing and presentation to T cells.
- Pathogen (microbial or danger) sensing and co-stimulation.
- Activation of other cell population belonging either to innate or adaptive immunity.
DCs functions: Antigen presentation to naïve T cells in initiaton of T cells response to protein antigens (priming).
Macrophages function: Antigen presentation to CD4+ T cells in effector phase of cell mediated immune response (T cell-enhanced killing of phagocytosed microbes).
B lymphocytes function: Antigen presentation to CD4+ T cells in humoral immune responses (helper T cells interactions).
Vascular endothelial cells function: Promote activation of antigen-specific T cells at site of antigen exposure.
Various epithelial and mesenchymal cells may have a role in inflammatory diseases.
Antigen recognition by T cells
T cell receptor only recognise antigens associated to cell structures. Cell proteins responsible for antigen presentation are encoded by MHC genes.
There are two main routes through which T cells recognise antigens:
- Endogenous pathway: comes from inside the cell. The antigen is processed into a peptide that binds usually to MHC-I and is therefore presented to CD8+ T cells.
- Exogenous pathway: The antigen comes from the extracellular environment and must be first digested by the cell (usually by phagocytosis). The antigen is processed into a peptide that binds to MHC-II molecules and is then presented to CD4+ T cell.
Maturation of DCs
Microbes bound to DC by pathogen associated molecular patterns (PAMPs) sitmulate the cell to mature, so it acquires the abilities to activate naïve T cells that eventually will become mature cytotoxic and helper T cells.
The binding of DCs to T cells induces the reorganisation of the microtubule organising centre of the dendritic cell. That, in turn, causes the redistribution of cytokine-containing secretory organelles within the DC’s cytoplasm and the cytokine is released directly in the interface between the two cells before diffusing to surrounding tissue fluid.
Mature dendritic cell is not able to take other antigens. However, it is able to activate T cells. In order to do that, DC must migrate.
Human MHC
MHC-I:
- HLA-A: Most polymorphic one
- HLA-B: Most polymorphic one
- HLA-C
MHC-II:
- HLA-DR
- HLA-DP
- HLA-Dq
MHC-III: Molecules related with immune response but not with antigen presentation.
All of them are located in chromosome 6
Properties of MHC genes
MHC genes encode two types of proteins structurally different but homologous.
MHC genes are highly polymorphic: Vary a lot between individuals of the same specie. The higher variability, the highest chance for survival of the specie.
MHC genes are co-dominantly expressed: All the genes of MHC are going to be expressed twice, poligenicity, which provides more chances for survival to the individual.
MHC structure
MHC type I is composed by two chains. Alpha chain (45 Kilo Daltons) and beta chain (12 Kilo Daltons)Alpha chain can be further divided into 3 domains of 90 amino acids. Alpha 1 and alpha 2 interact to form the groove in which the 8 to 10 amino acid antigenic peptide will be placed. Alpha 3 is highly conserved.
Beta subunit is formed by a beta-2-microglobulin.
MHC-I has a 25 aminoacid transmembrane domain and a 30 amino acid cytoplasmic domain. Alpha 1 and alpha 2 are the most polymorphic regions of MHC-I.
MHC type II is formed by two chains, alpha chain (33 kilo daltons) and beta chain (28 kilo daltons). Alpha chain can be further divided into two subunits: Alpha 1 and alpha 2. Beta chain can also be divided into two subunits: beta 1 and 2. In this case, the peptide-binding groove is formed by alpha 1 and beta 1 subunits and can bind to antigenic peptides going from 13 to 15 amino acids. MHC-II also has a transmembrane domain and a cytoplasmic one. Beta 1 is the most polymorphic region of MHC-II.
Celiac disease can be associated with…
HLA-DQB1 and HLA-DQ2
DR3
Which is the locus associated to recovery against malaria?
B53
Endogenous pathway
If a cell is infected by an intracellular pathogen, there will be pathogenic protein synthesis inside that cell. Viral mRNA is transported to the cytosol and converted into an antigenic peptide.
The protein is tagged by ubiquitin and enters to the proteasome, where it is proteolised and degraded into small peptides
Peptides will enter to the rough endoplasmic reticulum after being translocated by TAP (Transporter associated with antigen processing). TAP is an endoplasmic reticulum membrane-spanning heterodimer consisting of two proteins: TAP1 and TAP2. TAP has affinity for peptides containing from 8 to 16 amino acid although the optimal length is 9 amino acids. This fact is important because MHC-I peptide groove has room for peptides going from 8 to 10 amino acids. However, ERAP1 will process the peptide to a suitable size for MHC-I.
MHC-I molecules are synthesised without peptide recognising ability in rough endoplasmic reticulum.
After MHC is synthesised, calnexin, calreticulin and tapasin will fold this molecule and put it close to TAP.
MHC-I molecules and the peptide will form a complex thanks to chaperones molecules. The binding is really stable. This complex, that thanks to chaperones is able to cross RER membrane, will go to Golgi Apparatus and then to an exocytic vesicle.
MHC-I-peptide complex is expressed on the membrane of the cell.
Any of these steps can be interacted by a virus. If MHC-I levels are low, virus are more likely to interfere with antigen presentation processes.
Exogenous pathways
There are different ways to perform the exogenous pathway. Either an specific way or an unspecific one thanks to phagocytic activity. Anyway, the exogenous antigen will be internalised, processed and receptors will be recycled.
Internalised antigens are transformed into peptides thanks to endocytic vesicles. Early endosomes have an acidic pH going from 6 to 6.5. Late endosomes pH is even more acid, around 4,5 to 5. Endosomes will then fuese with lysosomes and the content will be degraded into peptides able to bind MHC-II molecules.
Simultaneously to this process, MHC-II molecules are synthesised and exported from endoplasmic reticulum in vesicles. Invariant chain or CD74 plays an important role in this step as it guide the transport of MHC-II molecule to the endocytic vesicles and prevents peptides from binding to early to MHC-II in the endoplasmic reticulum.
Invariant chain is degraded within the late endocytic compartments and CLIP is formed. CLIP remains in the peptide-binding groove of MHC-II until HLA-DM exchange it for antigenic peptide fragments. HLA-DM activity may be regulated by HLA-DO molecule in some APCs, specially in DCs. Invariant chain also serves as a chaperon in the binding of antigenic peptide and MHC-II in late endosomes.
The complex formed by MHC-II and the peptide is expressed on the surface of the cell membrane and presented to CD4+ cells.
