Cross-presentation
   HOME

TheInfoList



OR:

Cross-presentation is the ability of certain professional
antigen-presenting cell An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using ...
s (mostly dendritic cells) to take up, process and present ''extracellular'' antigens with
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 plat ...
molecules to CD8 T cells (cytotoxic T cells). Cross-priming, the result of this process, describes the stimulation of naive
cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating cells ...
CD8+ T cells into activated cytotoxic CD8+ T cells. This process is necessary for immunity against most tumors and against viruses that infect dendritic cells and sabotage their presentation of virus antigens. Cross presentation is also required for the induction of cytotoxic immunity by
vaccination Vaccination is the administration of a vaccine to help the immune system develop immunity from a disease. Vaccines contain a microorganism or virus in a weakened, live or killed state, or proteins or toxins from the organism. In stimulating ...
with protein antigens, for example, tumour vaccination. Cross-presentation is of particular importance, because it permits the presentation of exogenous antigens, which are normally presented by
MHC 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, ...
on the surface of dendritic cells, to also be presented through the
MHC 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 pla ...
pathway. The
MHC 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 pla ...
pathway is normally used to present endogenous antigens that have infected a particular cell. However, cross presenting cells are able to utilize the
MHC 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 pla ...
pathway in order to remain uninfected, while still triggering an
adaptive immune response The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...
of activated cytotoxic CD8+ T cells against infected peripheral tissue cells.


History

The first evidence of cross-presentation was reported in 1976 by Michael J. Bevan after injection of grafted cells carrying foreign minor histocompatibility (MHC) molecules. This resulted in a CD8+ T cell response induced by antigen-presenting cells of the recipient against the foreign MHC cells. Because of this, Bevan implied that these antigen presenting cells must have engulfed and cross presented these foreign MHC cells to host cytotoxic CD8+ cells, thus triggering an adaptive immune response against the grafted tissue. This observation was termed "cross-priming". Later, there had been much controversy about cross-presentation, which now is believed to have been due to particularities and limitations of some experimental systems used.


Cross-presenting cells

The primary and most efficient cross-presenting cells are
dendritic cell Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. ...
s, though
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s,
B lymphocyte B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
s and
sinusoidal endothelial cells A liver sinusoid is a type of capillary known as a sinusoidal capillary, discontinuous capillary or sinusoid, that is similar to a fenestrated capillary, having discontinuous endothelium that serves as a location for mixing of the oxygen-rich blo ...
have also been observed to cross present antigens in vivo and in vitro. However, in vivo dendritic cells have been found to be the most efficient and common antigen presenting cells to cross present antigens in MHC I molecules. There are two dendritic cells subtypes;
plasmacytoid Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific substa ...
(pDC) and
myeloid Myeloid tissue, in the bone marrow sense of the word '' myeloid'' ('' myelo-'' + ''-oid''), is tissue of bone marrow, of bone marrow cell lineage, or resembling bone marrow, and myelogenous tissue (''myelo-'' + '' -genous'') is any tissue of, ...
(mDC) dendritic cells. pDCs are found within the blood and are able to cross present antigens directly or from neighboring apoptotic cells, but the main physiological significance of pDCs is the secretion of type I IFN in response to bacterial infections. mDCs are categorized as migratory DCs, resident DCs, Langerhans cells, and inflammatory dendritic cells. All mDCs have specialized functions and secretory factors, but they are all still able to cross present antigens in order to activate cytotoxic CD8+ T cells. There are many factors that determine cross presentation function such as antigen uptake and processing mechanism, as well as environmental signals and activation of cross presenting dendritic cells. The activation of cross presenting dendritic cells is dependent on stimulation by CD4+ T helper cells. The co-stimulatory molecule CD40/CD40L along with the danger presence of an exogenous antigen are catalysts for dendritic cell licensing, and thus the cross presentation and activation of naive CD8+ cytotoxic T cells.


Vacuolar and cytosolic diversion

In addition to solid structure uptake, dendritic cell phagocytosis simultaneously modifies the kinetics of endosomal trafficking and maturation. As a consequence, external soluble antigens are targeted into the MHC class I cross-presentation pathway instead of the MHC Class II pathway. However, there is still uncertainty in regard to a mechanistic pathway for cross presentation within an antigen presenting cell. Currently, there are two main pathways proposed, cytosolic and vacuolar. The vacuolar pathway is initiated through the
endocytosis Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. E ...
of an extracellular antigen by a dendritic cell. Endocytosis results in the formation of a phagocytic vesicle, where an increasingly acidic environment along with the activation of enzymes such as lysosomal proteases triggers the degradation of antigen into peptides. The peptides can then be loaded onto MHC I binding grooves within the phagosome. It is unclear whether the MHC I molecule is being exported from the endoplasmic reticulum before peptide loading, or is being recycled from the cell membrane prior to peptide loading. Once the exogenous antigen peptide is loaded onto the MHC class I molecule, the complex is exported to the cell surface for antigen cross presentation presentation. There is also evidence that suggest that cross-presentation requires a separate pathway in a proportion of CD8(+) dendritic cells that are able to cross-present. This pathway is called the cytosolic diversion pathway. Similarly to the vacuolar pathway, antigens are taken into the cell through endocytosis. Antigen proteins are transported out of this compartment into the
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
by unknown mechanisms. Within the cytoplasm, exogenous antigens are processed 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 ...
and degraded into peptides. These processed peptides can either be transported by the
TAP transporter 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 ...
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 ( ...
, or back into the same endosome for loading onto MHC class I complexes,. It is believed that MHC I loading occurs both in the ER as well as phagocytic vesicles such as an endosome in the cytosolic pathway. For MHC class I loading within the Endoplasmic Reticulum, exogenous antigen peptides are loaded onto MHC class I molecules with the help of the peptide loading complex and chaperone proteins such as
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 ...
, ERAP,
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 maj ...
, and
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 ...
. After antigen peptide loading, the MHC molecule is transported out of the ER, through the Golgi complex, and then onto the cell surface for cross presentation. It appears that both pathways are able to occur within an antigen presenting cell, and may be influenced by environmental factors such as proteasome and phagocytic inhibitors.


Relevance for immunity

Cross-presentation has been shown to play a role in the immune defense against many
virus A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's 1 ...
es (
herpesvirus ''Herpesviridae'' is a large family of DNA viruses that cause infections and certain diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word ''ἕρπειν ...
,
influenzavirus ''Orthomyxoviridae'' (from Greek language, Greek ὀρθός, ''orthós'' 'straight' + μύξα, ''mýxa'' 'mucus') is a family of negative-sense single-stranded RNA virus, negative-sense RNA viruses. It includes seven genus, genera: ''Influenza ...
, CMV, EBV, SIV,
papillomavirus ''Papillomaviridae'' is a family of non- enveloped DNA viruses whose members are known as papillomaviruses. Several hundred species of papillomaviruses, traditionally referred to as "types", have been identified infecting all carefully inspected ...
, and others),
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
(listeria, salmonella, ''E. coli'', ''M. tuberculosis'', and others) and
tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
s (brain, pancreas, melanoma, leukemia, and others). Even though many viruses can inhibit and degrade dendritic cell activity, cross-presenting dendritic cells that are unaffected by the virus are able to intake the infected peripheral cell and still cross present the exogenous antigen to cytotoxic T cells. The action of cross priming can bolster immunity against antigens that target intracellular peripheral tissues that are unable to be mediated by antibodies produced through B cells. Also, cross-priming avoids viral immune evasion strategies, such as suppression of
antigen processing Antigen processing, or the cytosolic pathway, is an immunological process that prepares antigens for presentation to special cells of the immune system called T lymphocytes. It is considered to be a stage of antigen presentation pathways. This pro ...
. Consequently, immune responses against viruses that are able to do so, such as herpes viruses, are largely dependent on cross-presentation for a successful immune response. Overall, cross presentation aids in facilitating an adaptive immune response against intracellular viruses and tumor cells. Dendritic cell-dependent cross-presentation also has implications for
cancer immunotherapy Cancer immunotherapy (sometimes called immuno-oncology) is the stimulation of the immune system to treat cancer, improving on the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer im ...
vaccines. The injection of anti-tumor specific vaccines can be targeted to specific dendritic cell subsets within peripheral skin tissues, such as migratory dendritic cells and Langerhans cells. After vaccine induced activation, dendritic cells are able to migrate to lymph nodes and activate CD4+ T helper cells as well as cross prime CD8+ T cytotoxic cells. This mass generation of activated tumor specific CD8+ T cells increases anti-tumor immunity, and is also able to overcome many of the immune suppressive effects of tumor cells.


Relevance for immune tolerance

Cross-presenting dendritic cells have a significant impact on the promotion of central and peripheral
immune tolerance Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that would otherwise have the capacity to elicit an immune response in a given organism. It is induced by ...
. In
central tolerance In immunology, central tolerance (also known as negative selection) is the process of eliminating any ''developing'' T or B lymphocytes that are autoreactive, i.e. reactive to the body itself. Through elimination of autoreactive lymphocytes, tol ...
, dendritic cells are present within the
thymus The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or ''T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. ...
, or the location of T cell development and maturation. Thymic dendritic cells can intake dead medullary thymic epithelial cells, and cross present "self" peptides on MHC class I as a negative selection check on cytotoxic T cells that have a high affinity for self peptides. Presentation of tissue specific antigens is initiated by medullary thymic epithelial cells (mTEC), but is reinforced by thymic dendritic cells after expression of AIRE and engulfment of mTECs. Although the function of dendritic cells in central tolerance is still relatively unknown, it appears that thymic dendritic cells act as a complement to mTECs during negative selection of T cells. In regard to peripheral tolerance, peripheral tissue resting dendritic cells are able to promote self tolerance against cytotoxic T cells that have an affinity for self peptides. They can present tissue specific antigens within the lymph node in order to regulate T cytotoxic cells from initiating an adaptive immune response, as well as regulate T cytotoxic cells that have a high affinity for self tissues, but were still able to escape central tolerance. Cross-presenting DCs are able to induce anergy, apoptosis, or T regulatory states for high self affinity T cytotoxic cells. This has large implications for defense against auto immune disorders and regulation of self specific cytotoxic T cells.


References


External links

* {{MeSH name, Cross-Presentation Immunology