Antigen Processing and Presentation

Antigens must be processed and given to immune cells in order to activate the essential features of adaptive immunity (specificity, memory, diversity, and self/nonself discrimination). MHC class I and class II molecules on the surface of antigen-presenting cells (APCs) and other cells regulate antigen presentation. 

MHC class I and class II molecules work similarly: they deliver short peptides to the cell surface, where they are recognised by CD8+ (cytotoxic) and CD4+ (helper) T cells, respectively. The difference is that MHC class I peptides are endogenous, or intracellular, whereas MHC class II peptides are external, or extracellular. Exogenous antigens can also be presented by MHC class I molecules in a process known as cross-presentation. When endogenous antigens are degraded by autophagy, they can also be presented by MHC class II. 

MHC class I presentation: 
All nucleated cells express MHC class I molecules. MHC class I molecules are formed in the endoplasmic reticulum (ER) and are made up of two chains: a polymorphic heavy chain and a 2-microglobulin chain. Prior to interaction with the 2-microglobulin, the heavy chain is stabilised by the chaperone calnexin. These compounds are stabilised in the presence of peptides by chaperone proteins such as calreticulin, Erp57, protein disulfide isomerase (PDI), and tapasin. The peptide-loading complex is made up of TAP, tapasin, MHC class I, ERp57, and calreticulin (PLC). 

Different proteasomes generate peptides for MHC class-I presentation: Most cells express the 26S proteasome; many immune cells express the immunoproteasome; and thymic epithelial cells express the thymic-specific proteasome. 

Antigen presentation: 
MHC class I molecules on the surface of a single cell offer a readout of the expression level of up to 10,000 proteins. This array is interpreted by cytotoxic T lymphocytes and natural killer cells, allowing them to monitor internal activities and identify infection and cancer. 

As time passes, MHC class I complexes at the cell surface may dissolve, allowing the heavy chain to be internalised. When MHC class I molecules reach the endosome, they are transferred to the MHC class II presentation pathway. Some MHC class I molecules can be recycled and present endosomal peptides in a process known as cross-presentation. 

MHC class I polymorphism: 
HLA-A, HLA-B, and HLA-C genes encode human MHC class I molecules (HLA stands for 'Human Leukocyte Antigen,' which is the human analogue of MHC molecules present in most vertebrates). These genes are highly polymorphic, which means that each individual has a distinct collection of HLA alleles. Differential susceptibility to infection and autoimmune diseases may come from the vast diversity of peptides that may bind to MHC class I in different individuals, as a result of these polymorphisms. Furthermore, MHC class I polymorphisms make a perfect tissue match between donor and recipient very impossible and are hence responsible for transplant rejection. 

MHC class II presentation: 
MHC class II molecules are expressed by APCs such as dendritic cells (DC), macrophages, and B cells (as well as mesenchymal stromal cells, fibroblasts, and endothelial cells in response to IFN stimuli, as well as epithelial cells and enteric glial cells). MHC class II molecules bind to peptides produced from degraded proteins in the endocytic process. MHC class II complexes are made up of - and -chains that are assembled in the ER and are held together by an invariant chain. After that, the process of antigen presentation by MHC class II molecules follows the same pattern as MHC class I presentation. 

MHC class II polymorphism: 
Human MHC class II molecules, like the MHC class I heavy chain, are encoded by three polymorphic genes: HLA-DR, HLA-DQ, and HLA-DP. Different MHC class II alleles can be utilised as genetic markers for a variety of autoimmune diseases, possibly because of the peptides they include.