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Antigen processing, or the cytosolic pathway, is an immunological process that prepares
antigen In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
s for
presentation A presentation conveys information from a speaker to an audience. Presentations are typically demonstrations, introduction, lecture, or speech meant to inform, persuade, inspire, motivate, build goodwill, or present a new idea/product. Presenta ...
to special cells of the
immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...
called
T lymphocytes T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes A lymphocyte is a type of white blood cell (leukoc ...
. It is considered to be a stage of antigen presentation pathways. This process involves two distinct pathways for processing of antigens from an organism's own (self) proteins or
intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
pathogen In biology, a pathogen (, "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 theory of d ...
s (e.g.
virus A virus is a submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Viruses are ...
es), or from phagocytosed pathogens (e.g.
bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...
); subsequent presentation of these antigens on class I or class II
major histocompatibility complex The major histocompatibility complex (MHC) is a large Locus (genetics), locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for Cell (biology), cell surface proteins essential for the adaptive immune system. The ...
(MHC) molecules is dependent on which pathway is used. Both
MHC class I MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other being MHC class II) and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on ...
and II are required to bind antigens before they are stably expressed on a cell surface. MHC I antigen presentation typically (considering
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, th ...
) involves the endogenous pathway of antigen processing, and MHC II antigen presentation involves the exogenous pathway of antigen processing. Cross-presentation involves parts of the exogenous and the endogenous pathways but ultimately involves the latter portion of the endogenous pathway (e.g. proteolysis of antigens for binding to MHC I molecules). While the joint distinction between the two pathways is useful, there are instances where extracellular-derived peptides are presented in the context of MHC class I and cytosolic peptides are presented in the context of MHC class II (this often happens in
dendritic cells A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
).


The endogenous pathway

The endogenous pathway is used to present cellular
peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...
fragments on the cell surface on MHC class I molecules. If a virus had infected the cell, viral peptides would also be presented, allowing the immune system to recognize and kill the infected cell. Worn out proteins within the cell become
ubiquitin 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 19 ...
ated, marking them for
proteasome Proteasomes are essential protein complexes responsible for the degradation of proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are found inside all e ...
degradation. Proteasomes break the protein up into peptides that include some around nine amino acids long (suitable for fitting within the peptide binding cleft of MHC class I molecules).
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), a protein that spans the membrane of the
rough endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for "little n ...
, transports the peptides into the lumen of the rough endoplasmic reticulum (ER). Also within the rough ER, a series of chaperone proteins, including
calnexin Calnexin (CNX) is a 67kDa integral 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 calciu ...
, calreticulin, ERp57, and Binding immunoglobulin protein (BiP) facilitates the proper folding of class I MHC and its association with β2 microglobulin. The partially folded MHC class I molecule then interacts with TAP via tapasin (the complete complex also contains calreticulin and Erp57 and, in mice, calnexin). Once the peptide is transported into the ER lumen it binds to the cleft of the awaiting MHC class I molecule, stabilizing the MHC and allowing it to be transported to the cell surface by 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 Cell (biology), cells. Part of the endomembrane system in the cytoplasm, it protein targeting, packages proteins ...
.


The exogenous pathway

The exogenous pathway is utilized by specialized
antigen-presenting cell An antigen-presenting cell (APC) or accessory cell is a Cell (biology), cell that displays an antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize the ...
s to present peptides derived from proteins that the cell has endocytosed. The peptides are presented on MHC class II molecules. Proteins are endocytosed and degraded by acid-dependent proteases in
endosome Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of the endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membra ...
s; this process takes about an hour. The nascent MHC class II protein in the rough ER has its peptide-binding cleft blocked by Ii (the
invariant chain HLA class II histocompatibility antigen gamma chain also known as HLA-DR antigens-associated invariant chain or CD74 (Cluster of Differentiation 74), is a protein that in humans is encoded by the ''CD74'' gene. The invariant chain (Abbreviated Ii ...
; a trimer) to prevent it from binding cellular peptides or peptides from the endogenous pathway. The invariant chain also facilitates MHC class II's export from the ER in a vesicle. This fuses with a late endosome containing the endocytosed, degraded proteins. The invariant chain is then broken down in stages, leaving only a small fragment called "Class II-associated invariant chain peptide" ( CLIP) which still blocks the peptide binding cleft. An MHC class II-like structure,
HLA-DM HLA-DM (human leukocyte antigen DM) is an intracellular protein involved in the mechanism of antigen presentation on Antigen-presenting cell, antigen presenting cells (APCs) of the immune system. It does this by assisting in peptide loading of maj ...
, removes CLIP and replaces it with a peptide from the endosome. The stable MHC class-II is then presented on the cell surface.


Cross-presentation processing

In
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, th ...
, peptides derived from extracellular proteins are presented in the context of MHC class I. The cell starts off with the exogenous pathways but diverts the antigens (cytosolic diversion) to the endogenous pathway. This can allow the cell to skip the parts of the endogenous pathway that involve synthesis of antigens from the antigenic genes with cellular machinery upon infection, because the endogenous pathway can involve infection before being able to present antigens with MHC I, and cross-presentation saves them the effort needed for that and allows the professional antigen-presenting cells (dendritic cells) to process and present antigens without getting infected, which does not tend to happen to dendritic cells and is quite common scenario of antigen-processing using the endogenous pathway. Not all antigen-presenting cells utilize cross-presentation.


Viral evasion of antigen processing

Certain species in the Cytolomegavirus family can cause the infected cell to produce proteins like US2, 3, 6, and/or 11. US11 and US2 mislead MHC I to the cytoplasm; US3 inhibits the transportation of MHC I in the ER (a part of the endogenous pathway and cross-presentation); US6 blocks peptide transportation by TAP to MHC I.
Mycobacterium tuberculosis ''Mycobacterium tuberculosis'' (M. tb), also known as Koch's bacillus, is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, ''M. tuberculosis'' ha ...
inhibits phagosome-endosome fusion, thus avoiding being destroyed by the harsh environment of the phagosome.Deretic, V., & Fratti, R. A. (1999). Mycobacterium tuberculosis phagosome. Molecular microbiology, 31(6), 1603-1609. Chicago ICP47 from some herpesvirus block transport of the peptide by TAP. U21 from some human herpesvirus 7 binds and targets certain MHC I molecules for lysosomal degradation. E19 from some adenoviruses block the movement of MHC I to the proper locations for the endogenous pathway. Nef from some HIV strains enhance the movement of MHC molecules back into the cytoplasm, preventing them from presenting antigens.


The role of Langerhans' dendritic cells in antigen processing

Langerhans' cells are particular type of dendritic cells present in non lymphoid tissues together with interstitial cells. When these cells (in an immature state) come in contact with antigenic cells or disease causing viruses etc. these cells produce an inflammatory stimulus and start antigen processing and move toward lymph nodes where these APCs present antigen to mature T lymphocytes. T-dependent antigen – Antigens that require the assistance of T cells to induce the formation of specific antibodies. T-independent antigen – Antigens that stimulate B cells directly.


B-cell activation with B-T cell interactions

Lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), an ...
s are one of the five kinds of white blood cells or leukocytes, circulating in the blood. Although mature lymphocytes all look pretty much alike, they are diverse in their functions. The most abundant lymphocytes are: * B lymphocytes (often simply called B cells) *
T lymphocytes T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes A lymphocyte is a type of white blood cell (leukoc ...
(likewise called T cells) B cells are produced in the bone marrow. The precursors of T cells are also produced in the bone marrow but leave the bone marrow and mature in the thymus (which accounts for their designation). Each B cell and T cell is specific for a particular antigen, which simply means that each of these cells is able to bind to a particular molecular structure (such as an antigen). The specificity of binding resides in a specific receptor for antigen: the
B-cell receptor The B-cell receptor (BCR) is a transmembrane protein on the surface of a B cell. A B-cell receptor is composed of a membrane-bound immunoglobulin molecule and a signal transduction moiety. The former forms a type 1 Transmembrane protein, transmemb ...
(BCR) and the
T-cell receptor The T-cell receptor (TCR) is a protein complex, located on the surface of T cells (also called T lymphocytes). They are responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. ...
(TCR) for B and T cells, respectively. Both BCRs and TCRs share these properties: * They are integral membrane proteins. * They are present in thousands of identical copies exposed at the cell surface. * They are made before the cell ever encounters an antigen. * They are encoded by genes assembled by the recombination of segments of DNA.


How antigen receptor diversity is generated

Each receptor has a unique
binding site In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...
. This site binds to a portion of the antigen called an
antigenic determinant An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that binds to the epitope is called a paratope. Although ep ...
or
epitope An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that binds to the epitope is called a paratope. Although e ...
. The binding, like that between an enzyme and its substrate, depends on complementarity of the surface of the receptor and the surface of the epitope and occurs mainly by non-covalent forces. Successful binding of the antigen receptor to the epitope, if accompanied by additional signals, results in: # Stimulation of the cell to leave G0 and enter the
cell cycle The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...
. # Repeated
mitosis Mitosis () is a part of the cell cycle in eukaryote, eukaryotic cells in which replicated chromosomes are separated into two new Cell nucleus, nuclei. Cell division by mitosis is an equational division which gives rise to genetically identic ...
leads to the development of a clone of cells bearing the same antigen receptor; that is, a clone of cells of the identical specificity. BCRs and TCRs differ in: * their structure * the
genes In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
that encode them * the type of
epitope An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that binds to the epitope is called a paratope. Although e ...
to which they bind


B cells

BCRs bind intact antigens (like diphtheria toxoid, the protein introduced in the diphtheria-tetanus-pertussis vaccine). These may be soluble molecules present in the extracellular fluid; or intact molecules that the B cell plucks from the surface of antigen-presenting cells like macrophages and dendritic cells. The bound antigen molecules are engulfed into the B cell by receptor-mediated endocytosis. The antigen is digested into peptide fragments by various proteasomes and is then displayed at the cell surface attached along with a class II histocompatibility molecule. Helper T cells specific for this structure (i.e., with complementary TCRs) bind this B cell and secrete lymphokines that: # Stimulate the B cell to enter the cell cycle # The B cell undergoes repeated
mitotic Mitosis () is a part of the cell cycle in eukaryotic cells in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis is an equational division which gives rise to genetically identical cells in which the t ...
cell division Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...
, resulting in a clone of cells with identical BCRs; # The B cells switch from synthesizing their BCRs as integral membrane proteins to a soluble version; # The clonal cells differentiate into plasma cells that secrete these soluble BCRs, which we now call
antibodies An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...


T cells

There are two types of T cells that differ in their TCR: # alpha/beta (αβ) T cells: Their TCR is a heterodimer of an alpha chain with a beta chain. Each chain has a variable (V) region and a constant (C) region. The V regions each contain 3 hypervariable regions that make up the antigen-binding site. # gamma/delta (γδ) T cells: Their TCR is also a heterodimer of a gamma chain paired with a delta chain. They show characteristics of both innate immune response and acquired immune response; hence, regarded as the bridging between the two immune systems. The discussion that follows now concerns alpha/beta T cells. The TCR (of αβ T-cells) binds a bimolecular complex displayed at the surface of some other cells called an
antigen-presenting cell An antigen-presenting cell (APC) or accessory cell is a Cell (biology), cell that displays an antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize the ...
(APC). This complex consists of: a fragment of an antigen lying within the groove of a
histocompatibility Histocompatibility, or tissue compatibility, is the property of having the same, or sufficiently similar, alleles of a set of genes called human leukocyte antigens (HLA), or major histocompatibility complex (MHC). Each individual expresses many uni ...
molecule. The complex has been compared to a "hot dog in a bun".


See also

*
Major histocompatibility complex The major histocompatibility complex (MHC) is a large Locus (genetics), locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for Cell (biology), cell surface proteins essential for the adaptive immune system. The ...
(MHC) *
T cell T cells (also known as T lymphocytes) are an important part 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 receptor (TCR) on their cell ...
*
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, th ...
*
Antigen-presenting cell An antigen-presenting cell (APC) or accessory cell is a Cell (biology), cell that displays an antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize the ...
*
Antigen presentation Antigen presentation is a vital immune process that is essential for T cell immune response triggering. Because T cells recognize only fragmented antigens displayed on cell surfaces, antigen processing must occur before the antigen fragment can ...
*
Polyclonal response Polyclonal B cell response is a natural mode of immune response exhibited by the adaptive immune system of mammals. It ensures that a single antigen is recognized and attacked through its overlapping parts, called epitopes, by multiple Clone (B-c ...


References

*


External links

* {{MeSH name, Antigen+Processing Immune system