See also Class II MHC molecuels. 

MHC class I molecules bind cytosolically derived peptides within the endoplasmic reticulum (ER) and present them at the cell surface to cytotoxic T cells. (Williams “Assembly of MHC class I molecules within the endoplasmic reticulum” 2006;35(1-2):151-62). 

Structure: 

MHC Class 1 molecules have an ? chain having 3 external domains (?1-3), a transmembrane domain followed by a cytoplasmic domain and a ?2 microglobulin molecule (which is located on a separate chromosome) that does not contain a transmembrane region and is noncovalently bound to the ?3 domain.  The peptide binding cleft is located on the top surface of the class I MHC molecule and is large enough to bind a peptide of 8-10 amino acids. Each type of class I MHC molecule (K, D, and L in mice or A, B, and C in humans) binds a unique set of peptides. Each allelic variant (e.g., H-2KK and H-2Kd) also binds a distinct set of peptides. Since there are thousands of copies of each class I molecule, many different peptides will be expressed simultaneously on the surface of a nucleated cell by class I MHC molecules. 

All peptides, however, presented by class I molecules have conserved residues (anchor residues).

Class I major histocompatibility complex (MHC) molecuesl, designated HLA class I in huamns, bind and display peptide antigen ligands upon the cell surface. The peptide antigen ligands presented by the class I MHC are derived form either normal endogenous proteins (“self”) or foreign proteins (“nonself”) intorduced into the cell. Nonself protiens may be products of malignant transformation or intracellular pathogens such as viruses. In this manner, class I MHC molecuels covney information regarding the internal milieu fo a cell to immuen effector cells including but not limited to CD8+ cytotoxic T lymphocytes (CTLs), which are activated upon interation with “nonself” peptides, thereby lysing or killing the cell presenting such “nonself” peptides. Weidanz (US 2006/0034850)

Possible origins/sources of antigenic peptides for MHC I molecules

cytosolic proteins (endogenous or viral)

Alternative transcripts and defective proteins:

Proteins in ER: 

Endocytosed proteins: Proteins transferred from outside the cell.

MHCI antigen processing pathway

MHC glycoproteins bind peptides and present those peptides to .  Both direct and cross-presentation lead to the cell surface epxression of viral peptide-MHC complexes along with costimulatory molecules, such as CD80 and/or CD86, needed to activate naive T cells that engage the DC. 

Direct priming: Class I MHC molecules bind peptides derived from endogenous antigens that have been processed within the cytoplasm of the cell (e.g., normal cellular proteins, tumor proteins or viral and bacterial proteins produced within infected cells)  If a cell is a healthy cell, its class I molecules will display self peptides derived from common intracellular peptides. But if a cell has been infected by a virus, then viral peptides, as well as self peptides, will be displayed by its class I MHC molecules. In direct priming, viral proteins translated by infected cells are degraded by proteasomes into peptides that are transported into the ER, where thyey are loaded onto MHC class I molcules that are carried to the cell surface.

Cross-priming: Even if a virus fails to infect an APC directly, a successful immune response can nonetheless be mounted. This is provided when APCs acquire dying cells whose death may be the consequence of the virus infection. The ability of APCs to acquire such cell remnants by phagocytosis and then present processed materials derived form these cell remnants by means of class I MHC molecuels is called cross-presentation. In cross-priming, exogenous viral proteins are acquired from virus-infected cells by DCs. Exogenous proteins are delivered to the cytosol where they are processed by proteasomes into peptides. It is not clear yet whether peptides follow the standard pathway at this point or are delivered to MHC class I molcules in phagosomal compartments that then are delviered to the cell surface by a newly identified route. 

Most somatic cells express class I MHC molecules but the level of expression differs among different cell types. The highest level is expressed by . 

Intracellular proteins are degraded into short peptides by a cytosolic proteolytic system present in all cells. Those proteins destined for proteolysis often have ubiquitin attached to them. Ubiquitin-protein conjugates are degraded in a protease complex called a  proteasome. The particular proteasomes involved in antigen processing include 2 subunits encoded within the MHC gene cluster, LMP2 and LMP7 which are induced by increased levels of the T cell cytokines IFN-?. Association of these subunits with a proteasome changes its catalytic specificity to favor production of peptides that bind to class I MHC molecules. 

Proteins generated in the cytosol by the proteasome are translocated into the RER by TAP (transporter associated with antigen processing) which are ABC transporters located in the ER membrane. Once proteins get into ER, there are proteases (ER aminopeptidase)in the ER which trim the proteins. The assembly process of the class I MHC molecule within the RER membrane requires molecular chaperones which facilitate the folding of polypeptides. 

T cells can also proliferate in the presence of nonprotein antigens like glycolipids derived from bacteria such as TB. These nonproteins are presented by members of the CD1 family of nonclassical class 1 molecules. The CD1 family associates with  ?2 microglobulin and has general structural similarity to class I molecules. These genes are located not within the MHC but on chromosome 1.