MHC class I molecules are one of two primary classes of major histocompatibility complex
molecules and are found on nearly every nucleated cell of the body.
Their function is to display fragments of proteins from within the cell to T cells;
healthy cells will be ignored, while cells containing foreign proteins will be attacked
by the immune system.
Because MHC class I molecules present peptides derived from cytosolic proteins, the pathway
of MHC class I presentation is often called the cytosolic or endogenous pathway.
Function Class I MHC molecules bind peptides generated
mainly from degradation of cytosolic proteins by the proteasome.
The MHC I:peptide complex is then inserted into the plasma membrane of the cell.
The peptide is bound to the extracellular part of the class I MHC molecule.
Thus, the function of the class I MHC is to display intracellular proteins to cytotoxic
T cells.
However, class I MHC can also present peptides generated from exogenous proteins, in a process
known as cross-presentation.
A normal cell will display peptides from normal cellular protein turnover on its class I MHC,
and CTLs will not be activated in response to them due to central and peripheral tolerance
mechanisms.
When a cell expresses foreign proteins, such as after viral infection, a fraction of the
class I MHC will display these peptides on the cell surface.
Consequently, CTLs specific for the MHC:peptide complex will recognize and kill the presenting
cell.
Alternatively, class I MHC itself can serve as an inhibitory ligand for natural killer
cells.
Reduction in the normal levels of surface class I MHC, a mechanism employed by some
viruses during immune evasion or in certain tumors, will activate NK cell killing.
Structure MHC class I molecules consist of two polypeptide
chains, α and β2-microglobulin.
The two chains are linked noncovalently via interaction of b2m and the α3 domain.
Only the α chain is polymorphic and encoded by a HLA gene, while the b2m subunit is not
polymorphic and encoded by the Beta-2 microglobulin gene.
The α3 domain is plasma membrane-spanning and interacts with the CD8 co-receptor of
T-cells.
The α1 and α2 domains fold to make up a groove for peptides to bind.
MHC class I molecules bind peptides that are 8-10 amino acid in length.
Production
The peptides are generated mainly in the cytosol by the proteasome.
The proteasome is a macromolecule that consists of 28 subunits, of which half affect proteolytic
activity.
The proteasome degrades intracellular proteins into small peptides that are then released
into the cytosol.
The peptides have to be translocated from the cytosol into the endoplasmic reticulum
to meet the MHC class I molecule, whose peptide-binding site is in the lumen of the ER.
They have membrane proximal Ig fold.
Translocation and peptide loading The peptide translocation from the cytosol
into the lumen of the ER is accomplished by the transporter associated with antigen processing.
TAP is a member of the ABC transporter family and is a heterodimeric multimembrane-spanning
polypeptide consisting of TAP1 and TAP2.
The two subunits form a peptide binding site and two ATP binding sites that face the cytosol.
TAP binds peptides on the cytoplasmic side and translocates them under ATP consumption
into the lumen of the ER.
The MHC class I molecule is then, in turn, loaded with peptides in the lumen of the ER.
The peptide-loading process involves several other molecules that form a large multimeric
complex consisting of TAP, tapasin, calreticulin, calnexin, and Erp57.
Calnexin acts to stabilize the class I MHC α chains prior to β2m binding.
Following complete assembly of the MHC molecule, calnexin dissociates.
The MHC molecule lacking a bound peptide is inherently unstable and requires the binding
of the chaperones calreticulin and Erp57.
Additionally, tapasin binds to the MHC molecule and serves to link it to the TAP proteins,
thus facilitating enhanced peptide loading and colocalization.
Once the peptide is loaded onto the MHC class I molecule, the complex dissociates and it
leaves the ER through the secretory pathway to reach the cell surface.
The transport of the MHC class I molecules through the secretory pathway involves several
posttranslational modifications of the MHC molecule.
Some of the posttranslational modifications occur in the ER and involve change to the
N-glycan regions of the protein, followed by extensive changes to the N-glycans in the
Golgi apparatus.
The N-glycans mature fully before they reach the cell surface.
Peptide removal Peptides that fail to bind MHC class I molecules
in the lumen of the endoplasmic reticulum are removed from the ER via the sec61 channel
into the cytosol, where they might undergo further trimming in size, and might be translocated
by TAP back into ER for binding to an MHC class I molecule.
For example, an interaction of sec61 with bovine albumin has been observed.
Effect of viruses MHC class I molecules are loaded with peptides
generated from the degradation of ubiquitinated cytosolic proteins in proteasomes.
As viruses induce cellular expression of viral proteins, some of these products are tagged
for degradation, with the resulting peptide fragments entering the endoplasmic reticulum
and binding to MHC I molecules.
It is in this way, the MHC class I-dependent pathway of antigen presentation, that the
virus infected cells signal T-cells that abnormal proteins are being produced as a result of
infection.
The fate of the virus-infected cell is almost always induction of apoptosis through cell-mediated
immunity, reducing the risk of infecting neighboring cells.
As an evolutionary response to this method of immune surveillance, many viruses are able
to down-regulate or otherwise prevent the presentation of MHC class I molecules on the
cell surface.
In contrast to cytotoxic T lymphocytes, Natural killer cells are normally inactivated upon
recognizing MHC I molecules on the surface of cells.
Therefore, in the absence of MHC I molecules, NK cells are activated and recognize the cell
as aberrant, suggesting they may be infected by viruses attempting to evade immune destruction.
Several human cancers also show down-regulation of MHC I, giving transformed cells the same
survival advantage of being able to avoid normal immune surveillance designed to destroy
any infected or transformed cells.
Genes and isotypes Very polymorphic
HLA-A HLA-B
HLA-C
Less polymorphic HLA-E
HLA-F HLA-G
HLA-K HLA-L
Additional images References
External links Histocompatibility Antigens Class I at the
US National Library of Medicine Medical Subject Headings
MHC Class I Genes at the US National Library of Medicine Medical Subject Headings