Cross-presentation

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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 result of this process, describes the stimulation of naive cytotoxic CD8+ T cells into activated cytotoxic CD8+ T cells. [1] This process is necessary for immunity against most tumors [2] and against viruses that infect dendritic cells and sabotage their presentation of virus antigens. [3] [4] Cross presentation is also required for the induction of cytotoxic immunity by vaccination with protein antigens, for example, tumour vaccination. [5]

Contents

Cross-presentation is of particular importance, because it permits the presentation of exogenous antigens, which are normally presented by MHC II on the surface of dendritic cells, to also be presented through the MHC I pathway. [6] The MHC I 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 pathway to present exogenous antigens (ones not from the cell itself) to trigger an adaptive immune response by activating cytotoxic CD8+ T cells recognizing the exogenous antigens on the MHC class I complexes.

History

The first evidence of cross-presentation was reported in 1976 by Michael J. Bevan after injection of grafted cells carrying foreign minor histocompatibility (MiHA) molecules. This resulted in a CD8+ T cell response induced by antigen-presenting cells of the recipient against the foreign MiHA cells. [7] Because of this, Bevan implied that these antigen presenting cells must have engulfed and cross presented these foreign MiHA cells to host cytotoxic CD8+ cells, thus triggering an adaptive immune response against the grafted tissue. This observation was termed "cross-priming". [8] [7]

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. [9]

Cross-presenting cells

The primary and most efficient cross-presenting cells are dendritic cells, though macrophages, B lymphocytes and sinusoidal endothelial cells 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. [6] There are two dendritic cells subtypes; plasmacytoid (pDC) and myeloid (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 viral infections. [10] 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. [10]

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. [11]

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.[ citation needed ] 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. [6]

The vacuolar pathway is initiated through the endocytosis of an extracellular antigen by a dendritic cell. [6] 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. [6] 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. [6] 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.

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.[ citation needed ] This pathway is called the cytosolic diversion pathway. [10] Similarly to the vacuolar pathway, antigens are taken into the cell through endocytosis. Antigen proteins are transported out of this compartment into the cytoplasm by unknown mechanisms. Within the cytoplasm, exogenous antigens are processed by the proteasome and degraded into peptides. [10] These processed peptides can either be transported by the TAP transporter into the endoplasmic reticulum, [12] [13] or back into the same endosome for loading onto MHC class I complexes,. [14] 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. [10] 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, ERAP, tapasin, and calreticulin. [10] 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. [10]

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. [6]

Relevance for immunity

Cross-presentation has been shown to play a role in the immune defense against many viruses (herpesvirus, influenzavirus, CMV, EBV, SIV, papillomavirus, and others), bacteria (listeria, salmonella, E. coli, M. tuberculosis, and others) and tumors (brain, pancreas, melanoma, leukemia, and others). [15] [16] 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. [17] 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. [17] Also, cross-priming avoids viral immune evasion strategies, such as suppression of antigen processing. 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. [6]

Dendritic cell-dependent cross-presentation also has implications for cancer immunotherapy 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. [10] 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. [10]

Relevance for immune tolerance

Cross-presenting dendritic cells have a significant impact on the promotion of central and peripheral immune tolerance. In central tolerance, dendritic cells are present within the thymus, 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. [6] 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. [6] 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. [6] 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. [18]

Related Research Articles

<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

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.

<span class="mw-page-title-main">Dendritic cell</span> Accessory cell of the mammalian immune system

A dendritic cell (DC) is an antigen-presenting 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. They act as messengers between the innate and adaptive immune systems.

<span class="mw-page-title-main">T cell</span> White blood cells of the immune system

T cells are one of the important types of 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 receptor (TCR) on their cell surface.

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous 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 pathogens (such as viruses or bacteria), or cells that are damaged in other ways.

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

<span class="mw-page-title-main">Major histocompatibility complex</span> Cell surface proteins, part of the acquired immune system

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 called MHC molecules.

<span class="mw-page-title-main">Adaptive immune system</span> Subsystem of the immune system

The adaptive immune system, AIS, also known as the acquired immune system, or specific immune system is a subsystem of the immune system that is composed of specialized cells, organs, and processes that eliminate pathogens specifically. The acquired immune system is one of the two main immunity strategies found in vertebrates.

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 process involves two distinct pathways for processing of antigens from an organism's own (self) proteins or intracellular pathogens, or from phagocytosed pathogens ; subsequent presentation of these antigens on class I or class II major histocompatibility complex (MHC) molecules is dependent on which pathway is used. Both MHC class I and II are required to bind antigens before they are stably expressed on a cell surface. MHC I antigen presentation typically 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.

<span class="mw-page-title-main">Antigen-presenting cell</span> Cell that displays antigen bound by MHC proteins on its surface

An antigen-presenting cell (APC) or accessory cell is a 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 these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T cells.

<span class="mw-page-title-main">MHC class I</span> Protein of the immune system

MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on platelets, but not on red blood cells. Their function is to display peptide fragments of proteins from within the cell to cytotoxic T cells; 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 peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called cytosolic or endogenous pathway.

<span class="mw-page-title-main">Antigen presentation</span> Vital immune process that is essential for T cell immune response triggering

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 be recognized by a T-cell receptor. Specifically, the fragment, bound to the major histocompatibility complex (MHC), is transported to the surface of the antigen-presenting cell, a process known as presentation. If there has been an infection with viruses or bacteria, the antigen-presenting cell will present an endogenous or exogenous peptide fragment derived from the antigen by MHC molecules. There are two types of MHC molecules which differ in the behaviour of the antigens: MHC class I molecules (MHC-I) bind peptides from the cell cytosol, while peptides generated in the endocytic vesicles after internalisation are bound to MHC class II (MHC-II). Cellular membranes separate these two cellular environments - intracellular and extracellular. Each T cell can only recognize tens to hundreds of copies of a unique sequence of a single peptide among thousands of other peptides presented on the same cell, because an MHC molecule in one cell can bind to quite a large range of peptides. Predicting which antigens will be presented to the immune system by a certain MHC/HLA type is difficult, but the technology involved is improving.

<span class="mw-page-title-main">MHC class II</span> Protein of the immune system

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, macrophages, some endothelial cells, thymic epithelial cells, and B cells. These cells are important in initiating immune responses.

Understanding of the antitumor immunity role of CD4+ T cells has grown substantially since the late 1990s. CD4+ T cells (mature T-helper cells) play an important role in modulating immune responses to pathogens and tumor cells, and are important in orchestrating overall immune responses.

In immunology, peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery. Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Peripheral tolerance can also serve a purpose in preventing an immune response to harmless food antigens and allergens.

<span class="mw-page-title-main">Cancer immunology</span> Study of the role of the immune system in cancer

Cancer immunology (immuno-oncology) is an interdisciplinary branch of biology and a sub-discipline of immunology that is concerned with understanding the role of the immune system in the progression and development of cancer; the most well known application is cancer immunotherapy, which utilises the immune system as a treatment for cancer. Cancer immunosurveillance and immunoediting are based on protection against development of tumors in animal systems and (ii) identification of targets for immune recognition of human cancer.

Gamma delta T cells are T cells that have a γδ T-cell receptor (TCR) on their surface. Most T cells are αβ T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, γδ T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells. Their highest abundance is in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

Priming is the first contact that antigen-specific T helper cell precursors have with an antigen. It is essential to the T helper cells' subsequent interaction with B cells to produce antibodies. Priming of antigen-specific naive lymphocytes occurs when antigen is presented to them in immunogenic form. Subsequently, the primed cells will differentiate either into effector cells or into memory cells that can mount stronger and faster response to second and upcoming immune challenges. T and B cell priming occurs in the secondary lymphoid organs.

Immunoevasins are proteins expressed by some viruses that enable the virus to evade immune recognition by interfering with MHC I complexes in the infected cell, therefore blocking the recognition of viral protein fragments by CD8+ cytotoxic T lymphocytes. Less frequently, MHC II antigen presentation and induced-self molecules may also be targeted. Some viral immunoevasins block peptide entry into the endoplasmic reticulum (ER) by targeting the TAP transporters. Immunoevasins are particularly abundant in viruses that are capable of establishing long-term infections of the host, such as herpesviruses.

Tolerogenic dendritic cells are heterogenous pool of dendritic cells with immuno-suppressive properties, priming immune system into tolerogenic state against various antigens. These tolerogenic effects are mostly mediated through regulation of T cells such as inducing T cell anergy, T cell apoptosis and induction of Tregs. Tol-DCs also affect local micro-environment toward tolerogenic state by producing anti-inflammatory cytokines.

Cancer vaccine targeting CD4+ T cells is a type of vaccine used to treat existing cancer. Cancerous cells usually cannot be recognized by the human immune system, and therefore cannot be destroyed. Some researchers state that cancer can be treated by increasing the response of T cells, especially CD4+ T cells, to cancerous cells through cancer vaccine injection.

References

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