Antigen presentation and MHC

MHC expression

Major histocompatibility complex MHC IPresent on all nucleated cells 3 alpha subunits, alpha one non covalently bound to a beta 2 m subunit. Antigen binding site between alpha one and two. MHC IIPresent on antigen presenting cells - DCs, B cells, monocytes and macrophages - DCs present the most Consists of two alpha subunits, and two beta subunits, antigen binding is between the two at a groove. MHC is called HLA in humans. MHC exist in many allelic forms and are the most polymorphic genes found in our genome.  

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Antigen loading 

Exogenous antigen: Peptides generated in phagosomes bind MHC IIEndogenous antigen: Peptides generated in the cytoplasm bind MHC IHowever, there is an exception to this rule. In the case of DCs, virally infected, apoptotic cells are phagocytosed and digested, then loaded onto MHC II to present to CD4 helper cells. However, as DC are rarely infected by viruses, it must still present to CD8 cells. This is done by cross priming. When DC process dead, infected cells via the exogenous pathway, antigen leaks into the cytoplasm. This leaked antigen is treated as cytoplasmic and fed into the endogenous pathway to MHC I and CD8 cells. 

MHC structure

MHC IAt each pole of the peptide binding site, 2 amino acid residues are conserved, ensuring only short peptides are permitted inside the cleft. Anchoring residues also hold the peptide in place by weak electrostatic forces. Polymorphisms exist on the peptide contact face of alpha one and two subunits. MHC IIMuch the same as MHC I, however, long peptides reside through the binding site, permitted by the "extended open conformation. There are still anchoring residues that operate by weak electrostatic forces. Polymorphisms exist only on the peptide contact face of the beta 1 subunit.Variation in polymorphisms creates variation in binding affinity, enabling the immune system to target a wide variety of antigens by their respective binding affinities. The T cell receptor recognises the MHC and peptide as an entire complex 

MHC I/II and self antigen

Stable MHC I/II require peptide bound to antigen binding groove. Most 'empty' MHC is either recycled from the cell surface, or does not even reach the surface. To overcome this problem of stability, in the absence of chronic infection, MHC is loaded with self antigen. This covers 3 bases in immunity: maintain tolerance of self peptide given to T cells  surveillance of cancer cells  detection of silent infections

MHC antigen presentation pathway

MHC IEndogenous antigen is fragmented by a proteasome and fed into the ER by TAP transporter. A chaperone protein holds MHC I in place until peptide has bound, at which point its is translocated to the cell membrane. MHC IIExogenous antigen contained in the phagolysosome awaiting MHC II. MHC II sits on the edge of the ER with its binding site filled by a chaperone known as the invariant chain - Ii. It migrates to the phagolysosome where Ii is degraded by proteases and peptide fills the binding site. It is then translocated to the cell membrane.The invariant chain Ii, stabilizes immature MHC II and prevents premature loading of MHC II in its way to the phagolysosome.  Note there is still a fraction of the Ii that remains on MHC II binding groove, called Class II Invariant Chain Peptide (CLIP). DM is an MHC like molecule that catalyses the removal of CLIP and replaces it with antigenic peptide.