Lecture 6- Antigen presenting cells Flashcards
What are naked antigens?
Antigens that are not attached to any carrier molecule, exist in a free unbound form.
What is the difference between antigen binding with B cells and T cells?
Antibodies and B cell receptors can interact, recognise and bind antigens in their native state. However T cell receptors have an antigen binding site but will only recognise and bind to an antigen if it is presented in a specific and defined manner. So they will not bind to the antigen is its present on its own. It requires the antigen presenting mechanism (in a complex with MHC molecule).
What are the characteristics of the MHC?
First identified by their powerful effects on the immune response to transplanted tissues. MHC class I and II.
What is MHC encoded by?
Polygenic-encoded by several different MHC class I and II genes (more than 200 in humans) called human leukocyte antigens.
How polymorphic is MHC?
Highly- multiple allele variants of each gene within the population. Individuals are usually heterozygous (usually corresponding MHC locus on both chromosomes does not encode the same allele).
What is the structural similarity of MHC class I and II?
Structurally similar. Both present antigens to T cells by exposing a peptide binding cleft on their surface.
What is the structure of MHC class I?
Made up of a single alpha chain. The alpha chain forms the peptide-binding cleft. It is associated with beta-2 microglobulin which binds non covalently. Presents antigens to CD8+ T cells (cytotoxic T cells).
What is the structure of MHC class II?
Made up of 2 chains an alpha chain and a beta chain. Both chains contribute to the peptide-binding cleft. Expressed mainly on antigen presenting cells like macrophages, dendritic cells and B cells. Presents antigens to CD4+ T cells (helper T cells).
Where do peptides bind on the MHC classes?
MHC class 1 peptides bound by their ends. MHC class 2 peptides bound along their length.
Which molecules are rich in MHC?
T cells, B cells, myeloid cells (macrophages, dendritic cells). These are called professional antigen presenting cells.
What cells do MHC 1 bind to?
Cytosolic pathogens. e.g., shigella flexneri.
What cells do MHCII bind to?
Intravesicular pathogens, extracellular pathogens and toxins.
How does antigen presenting occur with MHC class 1?
Partially folded MHC class I alpha chains bind to calnexin until beta 2 microglubulin binds. This complex is released from calnexin, binds a complex of chaperone proteins (calreticullin, Erp57) and binds to TAP via tapasin. Cytosolic proteins are degraded to peptide fragments by the proteosome, a large multicatalytic protease. TAP delivers a peptide that binds to MHC class I molecule and completes its folding. The fully folded MHC class 1 molecules is released from the TAP complex and exported.
How does antigen presenting occur with MHC class II?
Antigen is taken up into intracellular vesicles. In early endosomes of neutral pH endosomal proteases are inactive. Acidification of vesicles activates proteases to degrade antigen into peptide fragments. Vesicles containing peptidese fuse with vesicles containing MHC class II molecules.
What uses MHC class II?
Pathogens in acidified endocytosed vesicles e.g., Mycobacteria in macrophages; eukaryotic parasites (recognised by CDC T cells). Acid proteases e.g., cysteine proteases: mainly Cathespins B, D, S and L.
What does the invariant chain do?
(Li, Leupeptin-induced peptide) targets delivery of MHC II to appropriate endosomal compartment for peptide loading. Li prevents premature binding of self peptides or other peptides to open ended MHC class II peptide binding groove during its synthesis in ER. Invariant chain blocks the groove. In the acidified vesicle invariant chain is cleaved in stages to produce a peptide class II invariant peptide or CLIP. CLIP-must be displaced for peptide to bind.
What is the role of HLA-DM in antigen processing via MHC II?
Catalyses peptide loading of MHC II release of CLIP and binding of other peptides. Binds to stabilise empty MHC class II molecules. Acidic environment delivered by endosome so that is why this is required.
What do antigen presenting cells do?
Trap antigen and migrate to the peripheral lymphoid organs e.g., lymph nodes. Present peptide fragments to naive T cells. Each type is specialised to process and present antigen from different sources to T cells.
What are the three main types?
- Dendritic cells- self antigen, protein antigen which trigger allergic responses, viral and bacterial antigens.
- Macrophages-intracellular bacterial antigens.
- B cells-soluble antigens
What happens in APC activation of T cells by co-stimulation?
Ligation of T cell receptor and CD4/CD8 co-receptor via MHC complex does NOT stimulate naive T cells to proliferate and differentiate into armed effectors. Antigen specific clonal expansion of naive T cells requires a second co-stimulatory signal on the APC.
What is the co-stimulatory signal?
B7 complex. A homordimeric glycoprotein B7.1 (CD80) and B7.2 (CD86). T cells have a B7 receptor called CD28.
What are dendritic cells?
Most potent APC for naive T cells. Actively take up antigen by phagocytosis. Infection stimulates migration to local lymphoid tissues where they express high levels of MHC class I and II and B7.
How do dendritic cells function?
Antigen uptake by langerhans cells in the skin. langerhans cells leave the skin and enter the lymphatic system. Langerhans cells enter the lypmh node to become dendritic cells expressing B7. B7-positive dendritic cells stimulate naive T cells.
What happens when a macrophage takes up a nonbacterial/ self protein?
Unstimulated macrophages do not deliver a co-stimulatory signal to T cells recognising nonbacterial antigen. leads to anergic T cells. Some proteins (self and foreign) fail to induce immune response, presumably because they fail to elicit co-stimulatory signal in APCs.
