MHC and antigen presentation Flashcards
which chromosome?
6 (one maternal and one paternal) on the short arm, expressed codominantly on each cell!!
How many genes per MHC?
3 from each chromosome -> 6 in total.
MHC-1 classes are HLA-A, HLA-B, HLA-C
MHC-2 classes are called-HLA-DP, HLA-DQ, HLA-DR
What can occur is a cell do not express MHC 1 molecules?
NK cells can kill it. Thinks it retarted with cancer or some virus shit
Structure of MHC1
MHC I occurs as an α chain composed of three domains—α1, α2, and α3. The α1 rests upon a unit of the non-MHC molecule β2 microglobulin (encoded on human chromosome 15). The α3 domain is transmembrane, anchoring the MHC class I molecule to the cell membrane. The peptide being presented is held by the floor of the peptide-binding groove, in the central region of the α1/α2 heterodimer (a molecule composed of two nonidentical subunits). The genetically encoded and expressed sequence of amino acids, the sequence of residues, of the peptide-binding groove’s floor determines which particular peptide residues it binds.
MHC class I molecules bind peptides that are 8-9 amino acid in length in its fixed pocket of ENDOGENOUS origin.
The MHC I molecules are synthesised in the RER where it first only consists of the a-chain and its 3 domains, stabilized by a chaperone called calnexin, which also prevents premature binding of peptides
Structure of MHC2
MHC class II is formed of two chains, α and β, each having two domains—α1 and α2 and β1 and β2—each chain having a transmembrane domain, α2 and β2, respectively, anchoring the MHC class II molecule to the cell membrane. The peptide-binding groove is formed of the heterodimer of α1 and β1. Can bind to 11-25 amino acids (open cleft) of EXOGENOUS origin.
Codominantly expressed
MHC class II molecules in humans have five to six isotypes.
What is the function of Beta-2 microglobulin?
Found on MHC1. β2 microglobulin lies beside the α3 chain on the cell surface. Unlike α3, β2 has no transmembrane region. Directly above β2 (that is, further away from the cell) lies the α1 chain, which itself is next to the α2.
CD8 bind to this part of MHC1.
Function of the invarient chain
The invariant chain (Abbreviated Ii) is a polypeptide involved in the formation and transport of MHC class II protein. The cell surface form of the invariant chain is known as CD74.
The nascent MHC class II protein in the rough ER binds a segment of the invariant chain (Ii; a trimer) in order to shape the peptide binding groove and prevent formation of a closed conformation. Binding to Ii might also prevent binding of peptides from the endogenous pathway to the groove of MHC class II. The invariant chain also facilitates MHC class II’s export from the ER in a vesicle. The signal for endosomal targeting resides in the cytoplasmic tail of the invariant chain. This fuses with a late endosome containing the endocytosed proteins. It is then cleaved by cathepsin S (cathepsin L in cortical thymic epithelial cells), leaving only a small fragment called CLIP which blocks peptide binding until HLA-DM interacts with MHC II, releasing CLIP and allowing other peptides to bind. The stable MHC class-II is then presented on the cell surface.
Function of CLIP in MHC2
CLIP or Class II-associated invariant chain peptide is the part of the invariant chain (Ii) that binds MHC class II groove and remains there until the MHC receptor is fully assembled. The purpose of CLIP is to prevent the binding of self-peptide fragments prior to MHC II localization within the endo/lysosome.
HLA-DM
HLA-DM (human leukocyte antigen DM) is an intracellular protein involved in peptide presentation by MHC class II. It is encoded by the genes HLA-DMA and HLA-DMB.
In the endosomes, HLA-DM functions by promoting the dissociation of the CLIP peptide (a place holder peptide) from MHC class II which allows endosomal peptides to bind. Possibly by its preferential binding of the open, peptide-less conformation of MHC class II, HLA-DM then catalyzes peptide exchange, favoring more stable peptide-MHC complexes (which are resistant to DM action). Thus, HLA-DM is thought to play an important role in “editing” the peptide repertoire.
From lecture:
HLA-DM:
1. Loads MHC II by peptides (similar to TAP in case of MHC I)
2. Doesn’t bind peptide
3. Remains in endosome – doesn’t travel onto the surface
HLA and their association with MHC1 and 2
THe HLA molecules are either denoted by a single letter (HLA - A, B or C), which classifies them as MHC I molecules, or by 2 letters (HLA - DP, DQ or DR) which classifies them as MHC II molecules)
antigen presentation and significance
ANTIGEN PRESENTATION
Genetically determined HLA molecules
present small antigen-peptides to T-cells
MHC I: HLA-A, -B, -C – endogenous ag by nucleated cells
MHC II: HLA-DP, -DR, -DQ – exogenous ag by APC
SIGNIFICANCE
Immune system is continously informed about the outer and inner environment of various human cells
mhc restriction
MHC-restricted antigen recognition, or MHC restriction, refers to the fact that a given T cell can interact with both the self-major histocompatibility complex molecule and the foreign peptide that is bound to it, but will recognize and respond to the antigen, only when it is bound to a particular MHC molecule
mhc is polygenic? polymorphic? and co-inherited..
A polygenic trait is one whose phenotype is influenced by more than one gene. Traits that display a continuous distribution, such as height or skin color, are polygenic (in this case HLA-A, HLA-B… etc)
Polymorphic genes means that in a population there is more than one allele at the locus for that trait. (2000++ allels for some genes such as HLA-A)
MHC1 vs. MHC2 peptide presentation
MHC 1 groove: fixed pocket size of peptide: 8-9 aminoacids source of peptide: endogenous peptide self, virus, intracellular / cytosol-located parasite, tumor. presented by.. on all nucleated cells
MHC-2
groove: open cleft
size of peptide: 11-25 aminoacids
source of peptide: exogenous peptide
extracellular bacteria and intracellular / lysosomal invaders
Presented by.. on antigen presenting cells (Macro, dendritic, B cells.
Comparison table btw MHC-1 and MHC2
Composition of the stable peptide-MHC complex: MHC-1: Polymorphic chain α and β2 microglobulin, peptide bound to α chain
MHC-2: Polymorphic chains α and β, peptide binds to both.
Origin of antigenic proteins:
MHC-1: cytosolic proteins (mostly synthetized by the cell; may also enter from the extracellular medium via phagosomes)
MHC-2: Proteins present in endosomes or lysosomes (mostly internalized from extracellular medium).
Enzymes responsible for peptide generation:
MHC-1: Cytosolic proteasome.
MHC-2: Proteases from endosomes and lysosomes (for instance, cathepsin).
Location of loading the peptide on the MHC molecule:
MHC-1: Endoplasmic reticulum
MHC-2: Specialized vesicular compartment.
Molecules implicated in transporting the peptides and loading them on the MHC molecules:
MHC-1: TAP (transporter associated with antigen processing) with chaperon waiting the transport
of a suitable peptide from the cytosol
MHC-2: DM, invariant chain
