MHC and Antigen Processing Flashcards
What are the 6 isotypes of MHC class 1?
HLA-A, B, C, E, F, G
What are the 5 isotypes of MHC class 2?
HLA-DP, DQ, DR, DM, and DO
For the 6 isotypes of MHC class 1 and 5 isotypes of MHC class 2, which are highly polymorphic, polymorphic, oligomorphic, and monomorphic?
Highly polymorphic: HLA-A, HLA-B, HLA-C, and HLA-DR (beta chain)
Polymorphic: HLA-DP and HLA-DQ
Oligomorphic: HLA-E, HLA-G HLA-DM, HLA-DO (beta chain), and HLA-DR (alpha chain)
Monomorphic: HLA-F, and HLA-DO (alpha chain)
What are the 2 components to inherited MHC diversity? Describe
Gene families: which consist of multiple, similar genes encoding the proteins
Genetic polymorphism: the presence, within the population, of multiple, alternative forms or alleles of a gene
Which of the MHC isoforms are most involved in antigen presentation?
Those that are highly polymorphic
For CD4 T cells: HLA-A, B, and C
For CD8 T cells: HLA-DP, DQ, and DR
For the purpose of organ transplantation which and how many HLA anitgens do you want to match at?
Must match at 6 HLA antigens, HLA-A, HLA-B, and HLA-DR. There are only 3 genes but we have 2 copies of each gene and they happen to be codominantly expressed
What is a haplotype?
A group of genes within an organism that was inherited together from a single parent. With respect to MHC this is a linked cluster of polymorphic genes all encoded on chromosome 6
What cells are you likely to find MHC class II expressed on?
- Some activated T cells
- B cells
- Macrophages/APCs
- Thymic epithelial cells
* MHC II can be induced in certain cell types by cytokines but expression is not constitutive
What cells are you likely to find MHC class I expressed on?
All nucleated cells in the body (so MHC I is not found in red blood cells)
What is the structure of an MHC class I molecule?
1 peptide called the alpha chain (encoded by 1 gene) which contains 3 globular domains called alpha 1, 2, and 3. The alpha chain complexes with beta-2 microglobulin. The peptide binding groove is between the alpha 1 and 2 domains
What is the structure of an MHC class II molecule?
Composed of 2 peptide chains called alpha and beta which both contain 2 globular domains called alpha 1 and 2 and beta 1 and 2, respectively. The peptide binding groove is located between the beta 1 and alpha 1 domains
What are the secondary structural characteristics of both MHC I and II with respect to the peptide binding groove?
Peptide binding groove is composed of 2 alpha helices that flank a beta sheet. Together they contain most of the variability which allows for specificity of antigen.
What is a key difference between MHC I and II in how they interact with antigen?
MHC I will bind peptide at both ends
MHC II will bind it just at one end
This means that the size of the peptides is more uniform for MHC I
What do the non-polymorphic areas of MHC interact with?
Also called the invariant region they will interact with the coreceptor CD4 for class II or CD8 for class I
What are 6 features of MHC?
- Broad specificity: many different peptides can bind to the same MHC molecule
- Each MHC molecule displays one peptide at a time
- MHC molecules bind only to peptides: (cannot bind carbs, nucleic acids, or lipids)
- Peptides are acquired during intracellular assembly
- Stable surface expression of MHC molecule requires bound peptide
- Very slow off-rate: MHC displays bound peptide long enough to be located by T cell
What is MHC restriction?
T cells are only able to recognize antigen presented by MHC only in the context of that individuals particular MHC isoform
What types of peptides does each class of MHC have a preference for?
MHC I: endogenous peptide
MHC II: exogenous peptide
*MHC can bind self peptide but this is not recognized by the immune system
What are the direct and indirect mechanisms by which a phagocytic cell recognizes antigen for internalization?
Direct: Toll-Like Receptor (TLR), scavenger receptor, and mannose receptors
Indirect: Binding of C3b and/or the Fc region of Ig
Macrophages use direct and indirect methods and dendritic cells use just direct methods
Describe the process by which exogenous antigen is processed and presented. 7 steps
- Recognition by PRRs on the surface of professional APCs causes internalization of the antigen.
- The endosome fuses with the lysosome which causes a decrease in pH and proteolytic enzymes, thus producing peptide fragments 8-25 AA long
- Synthesis of MHC II occurs in the R.E.R. along with an invariant chain which occludes the peptide binding cleft.
- MHC II + invariant chain are moved to the golgi where they are packaged into an exocytic vesicle which also contains HLA-DM and various proteases
- The proteases remove most of the invariant chain leaving behind just a short peptide that is bound to the peptide binding cleft called Class II-associated invariant chain peptide (CLIP)
- The phagolysosome fuses with the exocytic vesicle and subsequently HLA-DM catalyzes the removal of CLIP thus allow exogenous peptide to bind to MHC II.
- Binding of peptide to MHC II stabilizes MHC II and the exocytic vesicle fuses with the plasma membrane thus completing the presentation process
Describe the process by which endogenous protein/antigen is presented. 6 steps
- Cytosolic proteins become ubiquitinated and then targeted by the proteasome
- Peptides bind to the TAP transporter which is present on the R.E.R. membrane
- Synthesis of MHC I and beta-2 microglobulin occurs in the R.E.R. where they form a loose association with the TAP transporter
- Another protein called Tapasin forms a bridge between MHC I and TAP transporter to efficiently transfer peptide from TAP to MHC I
- Binding of peptide to MHC I causes beta-2 microglobulin to properly fold thus stabilizing the complex
- The MHC I molecule bound with peptide is then directly transported to the membrane for presentation
What is cross-presentation? How does it occur?
The process by which a dendritic cell presents exogenous antigen either by class I or II MHC. Involves the transfer of peptide from an endocytic vesicle to the cytoplasm (unclear exactly how this occurs)
Why is cross presentation important?
It allows a dendritic cell to simultaneously activate by CD4+ and CD8+ T lymphocytes