MHC class I molecules are one of two primary classes of
major histocompatibility complex
The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are calle ...
(MHC) molecules (the other being
MHC class II
MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, ...
) and are found on the
cell surface
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
of all
nucleated
The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, ha ...
cells in the bodies of
vertebrate
Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...
s.
They also occur on
platelet
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
s, but not on
red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
s. Their function is to display peptide fragments of proteins from within the cell to
cytotoxic T cells
A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pa ...
; this will trigger an immediate response from the immune system against a particular non-self antigen displayed with the help of an MHC class I protein. Because MHC class I molecules present
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
A ...
s derived from
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
ic proteins, the pathway of MHC class I presentation is often called ''cytosolic'' or ''endogenous pathway''.
In humans, the
HLAs corresponding to MHC class I are
HLA-A
HLA-A is a group of human leukocyte antigens (HLA) that are encoded by the HLA-A locus, which is located at human chromosome 6p21.3. HLA is a major histocompatibility complex (MHC) antigen specific to humans. HLA-A is one of three major types of ...
,
HLA-B
HLA-B (major histocompatibility complex, class I, B) is a human gene that provides instructions for making a protein that plays a critical role in the immune system. HLA-B is part of a family of genes called the human leukocyte antigen (HLA) compl ...
, and
HLA-C
HLA-C belongs to the MHC (human = HLA) class I heavy chain receptors. The C receptor is a heterodimer consisting of a HLA-C mature gene product and β2-microglobulin. The mature C chain is anchored in the membrane. MHC Class I molecules, like HLA ...
.
Function
Class I MHC molecules bind
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
A ...
s generated mainly from degradation of cytosolic proteins by the
proteasome
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by w ...
. The MHC I:peptide complex is then inserted via endoplasmic reticulum into the external plasma membrane of the cell. The epitope peptide is bound on extracellular parts of the class I MHC molecule. Thus, the function of the class I MHC is to display intracellular proteins to
cytotoxic T cell
A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pa ...
s (CTLs). However, class I MHC can also present peptides generated from exogenous proteins, in a process known as
cross-presentation Cross-presentation is the ability of certain professional antigen-presenting cells (mostly dendritic cells) to take up, process and present ''extracellular'' antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, the ...
.
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 presenting cells.
Alternatively, class I MHC itself can serve as an inhibitory ligand for
natural killer cells
Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...
(NKs). Reduction in the normal levels of surface class I MHC, a mechanism employed by some viruses and certain tumors to evade CTL responses, activates NK cell killing.
PirB and visual plasticity
Paired-immunoglobulin-like receptor B (PirB), an MHCI-binding receptor, is involved in the regulation of visual
plasticity
Plasticity may refer to:
Science
* Plasticity (physics), in engineering and physics, the propensity of a solid material to undergo permanent deformation under load
* Neuroplasticity, in neuroscience, how entire brain structures, and the brain it ...
.
PirB is expressed in the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
and diminishes
ocular dominance
Ocular dominance, sometimes called eye preference or eyedness, is the tendency to prefer visual perception, visual input from one eye to the other. It is somewhat analogous to the laterality of right- or left-handedness; however, the side of the d ...
plasticity
Plasticity may refer to:
Science
* Plasticity (physics), in engineering and physics, the propensity of a solid material to undergo permanent deformation under load
* Neuroplasticity, in neuroscience, how entire brain structures, and the brain it ...
in the developmental
critical period
In developmental psychology and developmental biology, a critical period is a maturational stage in the lifespan of an organism during which the nervous system is especially sensitive to certain environmental stimuli. If, for some reason, the org ...
and adulthood.
When the function of PirB was abolished in mutant mice,
ocular dominance
Ocular dominance, sometimes called eye preference or eyedness, is the tendency to prefer visual perception, visual input from one eye to the other. It is somewhat analogous to the laterality of right- or left-handedness; however, the side of the d ...
plasticity
Plasticity may refer to:
Science
* Plasticity (physics), in engineering and physics, the propensity of a solid material to undergo permanent deformation under load
* Neuroplasticity, in neuroscience, how entire brain structures, and the brain it ...
became more pronounced at all ages.
PirB loss of function mutant mice also exhibited enhanced
plasticity
Plasticity may refer to:
Science
* Plasticity (physics), in engineering and physics, the propensity of a solid material to undergo permanent deformation under load
* Neuroplasticity, in neuroscience, how entire brain structures, and the brain it ...
after monocular deprivation during the
critical period
In developmental psychology and developmental biology, a critical period is a maturational stage in the lifespan of an organism during which the nervous system is especially sensitive to certain environmental stimuli. If, for some reason, the org ...
.
These results suggest PirB may be involved in modulation of
synaptic plasticity
In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuit ...
in the
visual cortex
The visual cortex of the brain is the area of the cerebral cortex that processes visual information. It is located in the occipital lobe. Sensory input originating from the eyes travels through the lateral geniculate nucleus in the thalamus and ...
.
Structure
MHC class I molecules are heterodimers that consist of two polypeptide chains, α and β
2-microglobulin (B2M). The two chains are linked noncovalently via interaction of B2M and the α
3 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
β2 microglobulin (B2M) is a component of MHC class I molecules. MHC class I molecules have α1, α2, and α3 proteins which are present on all nucleated cells (excluding red blood cells). In humans, the β2 microglobulin protein is encoded by t ...
gene. The α
3 domain is plasma membrane-spanning and interacts with the
CD8
CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). Along with the TCR, the CD8 co-receptor plays a role in T cell signaling and aiding with cytotoxic T cell-antigen in ...
co-receptor of
T-cells
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...
. The α
3-CD8 interaction holds the MHC I molecule in place while the
T cell receptor
The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding b ...
(TCR) on the surface of the cytotoxic T cell binds its α
1-α
2 heterodimer ligand, and checks the coupled peptide for antigenicity. The α
1 and α
2 domains fold to make up a groove for peptides to bind. MHC class I molecules bind peptides that are predominantly 8-10 amino acid in length (Parham 87), but the binding of longer peptides have also been reported.
Synthesis
The peptides are generated mainly in the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
by the
proteasome
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by w ...
. The proteasome is a macromolecule that consists of 28 subunits, of which half affect
proteolytic
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, ...
activity. The proteasome degrades intracellular proteins into small peptides that are then released into the cytosol. Proteasomes can also ligate distinct peptide fragments (termed spliced peptides), producing sequences that are noncontiguous and therefore not linearly templated in the genome. The origin of spliced peptide segments can be from the same protein (cis-splicing) or different proteins (trans-splicing). The peptides have to be translocated from the cytosol into the
endoplasmic reticulum
The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...
(ER) 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
Transporter associated with antigen processing (TAP) protein complex belongs to the ATP-binding-cassette transporter family. It delivers cytosolic peptides into the endoplasmic reticulum (ER), where they bind to nascent MHC class I molecules.
T ...
(TAP). TAP is a member of the
ABC transporter
The ATP-binding cassette transporters (ABC transporters) are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. It is represented in all extant phyla, from prokaryotes to humans. ABC transp ...
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 called the
Peptide loading complex
The peptide-loading complex (PLC) is a short-lived, multisubunit membrane protein complex that is located in the endoplasmic reticulum (ER). It orchestrates peptide translocation and selection by MHC class I, major histocompatibility complex class ...
consisting of TAP,
tapasin
TAP-associated glycoprotein, also known as tapasin or TAPBP, is a protein that in humans is encoded by the ''TAPBP'' gene.
Function
The ''TAPBP'' gene encodes a transmembrane glycoprotein that mediates interaction between newly assembled majo ...
,
calreticulin
Calreticulin also known as calregulin, CRP55, CaBP3, calsequestrin-like protein, and endoplasmic reticulum resident protein 60 (ERp60) is a protein that in humans is encoded by the ''CALR'' gene.
Calreticulin is a multifunctional soluble prote ...
,
calnexin
Calnexin (CNX) is 67kDaintegral protein (that appears variously as a 90kDa, 80kDa, or 75kDa band on western blotting depending on the source of the antibody) of the endoplasmic reticulum (ER). It consists of a large (50 kDa) N-terminal calcium- bi ...
, and
Erp57
Protein disulfide-isomerase A3 (PDIA3), also known as glucose-regulated protein, 58-kD (GRP58), is an isomerase enzyme. This protein localizes to the endoplasmic reticulum (ER) and interacts with lectin chaperones calreticulin and calnexin (CNX) ...
(
PDIA3
Protein disulfide-isomerase A3 (PDIA3), also known as glucose-regulated protein, 58-kD (GRP58), is an isomerase enzyme. This protein localizes to the endoplasmic reticulum (ER) and interacts with lectin chaperones calreticulin and calnexin (CNX) ...
). 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 and facilitates the selection of peptide in an iterative process called peptide editing, 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 440px
Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical ...
to reach the cell surface. The transport of the MHC class I molecules through the secretory pathway involves several
posttranslational modification
Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosome ...
s 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 Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles ins ...
. 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 (ER) are removed from the ER via the
sec61
Sec61, termed SecYEG in prokaryotes, is a membrane protein complex found in all domains of life. As the core component of the translocon, it transports proteins to the endoplasmic reticulum in eukaryotes and out of the cell in prokaryotes. It is ...
channel into the cytosol,
where they might undergo further trimming in size, and might be translocated by TAP back into ER for binding to a MHC class I molecule.
For example, an interaction of sec61 with bovine
albumin
Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...
has been observed.
Effect of viruses
MHC class I molecules are loaded with peptides generated from the degradation of
ubiquitinated
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fou ...
cytosolic proteins in
proteasomes
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by whi ...
. 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
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
through
cell-mediated immunity
Cell-mediated immunity or cellular immunity is an immune response that does not involve antibodies. Rather, cell-mediated immunity is the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in ...
, 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
Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...
(NK) 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 that it 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-A is a group of human leukocyte antigens (HLA) that are encoded by the HLA-A locus, which is located at human chromosome 6p21.3. HLA is a major histocompatibility complex (MHC) antigen specific to humans. HLA-A is one of three major types of ...
)
** (
HLA-B
HLA-B (major histocompatibility complex, class I, B) is a human gene that provides instructions for making a protein that plays a critical role in the immune system. HLA-B is part of a family of genes called the human leukocyte antigen (HLA) compl ...
)
** (
HLA-C
HLA-C belongs to the MHC (human = HLA) class I heavy chain receptors. The C receptor is a heterodimer consisting of a HLA-C mature gene product and β2-microglobulin. The mature C chain is anchored in the membrane. MHC Class I molecules, like HLA ...
)
* Less polymorphic
** (
HLA-E
HLA class I histocompatibility antigen, alpha chain E (HLA-E) also known as MHC class I antigen E is a protein that in humans is encoded by the ''HLA-E'' gene. The human HLA-E is a non-classical MHC class I molecule that is characterized by a limit ...
)
** (
HLA-F
HLA class I histocompatibility antigen, alpha chain F is a protein that in humans is encoded by the ''HLA-F'' gene. It is an empty intracellular molecule that encodes a non-classical heavy chain anchored to the membrane and forming a heterodimer w ...
)
** (
HLA-G
HLA-G histocompatibility antigen, class I, G, also known as human leukocyte antigen G (HLA-G), is a protein that in humans is encoded by the ''HLA-G'' gene.
HLA-G belongs to the HLA nonclassical class I heavy chain paralogues. Classical HLA I pro ...
)
** (pseudogene)
** (pseudogene)
Evolutionary history
The MHC class I genes originated in the most
recent common ancestor
In biology and genetic genealogy, the most recent common ancestor (MRCA), also known as the last common ancestor (LCA) or concestor, of a set of organisms is the most recent individual from which all the organisms of the set are descended. The ...
of all
jawed vertebrates
Gnathostomata (; from Greek: (') "jaw" + (') "mouth") are the jawed vertebrates. Gnathostome diversity comprises roughly 60,000 species, which accounts for 99% of all living vertebrates, including humans. In addition to opposing jaws, living ...
, and have been found in all living jawed vertebrates that have been studied thus far.
Since their emergence in jawed vertebrates, this gene family has been subjected to many divergent evolutionary paths as
speciation
Speciation is the evolutionary process by which populations evolve to become distinct species. The biologist Orator F. Cook coined the term in 1906 for cladogenesis, the splitting of lineages, as opposed to anagenesis, phyletic evolution within ...
events have taken place. There are, however, documented cases of trans-species
polymorphisms in MHC class I genes, where a particular
allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
in an evolutionary related MHC class I gene remains in two species, likely due to strong pathogen-mediated
balancing selection Balancing selection refers to a number of selective processes by which multiple alleles (different versions of a gene) are actively maintained in the gene pool of a population at frequencies larger than expected from genetic drift alone. Balancing ...
by
pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
s that can infect both species.
Birth-and-death evolution is one of the mechanistic explanations for the size of the MHC class I gene family.
Birth-and-death of MHC class I genes
Birth-and-death evolution asserts that
gene duplication
Gene duplication (or chromosomal duplication or gene amplification) is a major mechanism through which new genetic material is generated during molecular evolution. It can be defined as any duplication of a region of DNA that contains a gene. ...
events cause the genome to contain multiple copies of a gene which can then undergo separate evolutionary processes. Sometimes these processes result in
pseudogenization (death) of one copy of the gene, though sometimes this process results in two new genes with divergent function. It is likely that human MHC class Ib loci (HLA-E, -F, and -G) as well as MHC class I pseudogenes arose from MHC class Ia loci (HLA-A, -B, and -C) in this birth-and-death process.
References
External links
*
*
{{Surface antigens
Genes
Immune system
Glycoproteins
Protein targeting
Single-pass transmembrane proteins