Antigen-presenting cell

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Antigen presentation stimulates immature T cells to become either mature "cytotoxic" CD8+ cells or mature "helper" CD4+ cells. Antigen presentation.svg
Antigen presentation stimulates immature T cells to become either mature "cytotoxic" CD8+ cells or mature "helper" CD4+ cells.

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 their T cell receptors (TCRs). APCs process antigens and present them to T-cells.

Contents

Almost all cell types can present antigens in some way. They are found in a variety of tissue types. Dedicated antigen-presenting cells, including macrophages, B cells and dendritic cells, present foreign antigens to helper T cells, while virus-infected cells (or cancer cells) can present antigens originating inside the cell to cytotoxic T cells. In addition to the MHC family of proteins, antigen presentation relies on other specialized signaling molecules on the surfaces of both APCs and T cells.

Antigen-presenting cells are vital for effective adaptive immune response, as the functioning of both cytotoxic and helper T cells is dependent on APCs. Antigen presentation allows for specificity of adaptive immunity and can contribute to immune responses against both intracellular and extracellular pathogens. It is also involved in defense against tumors. Some cancer therapies involve the creation of artificial APCs to prime the adaptive immune system to target malignant cells.

Types and functions

Antigen-presenting cells fall into two categories: professional and non-professional. Those that express MHC class II molecules along with co-stimulatory molecules and pattern recognition receptors are often called professional antigen-presenting cells. [1] The non-professional APCs express MHC class I molecules.

T cells must be activated before they can divide and perform their function. This is achieved by interacting with a professional APC which presents an antigen recognized by their T cell receptor. The APC involved in activating T cells is usually a dendritic cell. T cells cannot recognize (and therefore cannot respond to) "free" or soluble antigens. They can only recognize and respond to antigen that has been processed and presented by cells via carrier molecules like MHC molecules. Helper T cells can recognize exogenous antigen presented on MHC class II; cytotoxic T cells can recognize endogenous antigen presented on MHC class I. Most cells in the body can present antigen to CD8+ cytotoxic T cells via MHC class I; however, the term "antigen-presenting cell" is often used specifically to describe professional APCs. Such cells express MHC class I and MHC class II molecules and can stimulate CD4+ helper T cells as well as cytotoxic T cells. [2] [3]

APCs can also present foreign and self lipids to T cells and NK cells by using the CD1 family of proteins, which are structurally similar to the MHC class I family. [4]

Professional APCs

Professional APCs specialize in presenting antigens to T cells. [5] They are very efficient at internalizing antigens, either by phagocytosis (e.g. macrophages), or by receptor-mediated endocytosis (B cells), processing the antigen into peptide fragments and then displaying those peptides (bound to a class II MHC molecule) on their membrane. [1] The T cell recognizes and interacts with the antigen-class II MHC molecule complex on the membrane of the antigen-presenting cell. An additional co-stimulatory signal is then produced by the antigen-presenting cell, leading to activation of the T cell. The expression of co-stimulatory molecules and MHC class II are defining features of professional APCs. [1] All professional APCs also express MHC class I molecules as well. [2]

The main types of professional antigen-presenting cells are dendritic cells, macrophages and B cells. [1]

Dendritic cells (DCs)

Dendritic cells have the broadest range of antigen presentation and are necessary for activation of naive T cells. [1] DCs present antigen to both helper and cytotoxic T cells. They can also perform cross-presentation, a process by which they present exogenous antigen on MHC class I molecules to cytotoxic T cells. Cross-presentation allows for the activation of these T cells. [2] Dendritic cells also play a role in peripheral tolerance, which contributes to prevention of auto-immune disease. [6]

Prior to encountering foreign antigen, dendritic cells express very low levels of MHC class II and co-stimulatory molecules on their cell surface. These immature dendritic cells are ineffective at presenting antigen to T helper cells. Once a dendritic cell's pattern-recognition receptors recognize a pathogen-associated molecular pattern, antigen is phagocytosed and the dendritic cell becomes activated, upregulating the expression of MHC class II molecules. It also upregulates several co-stimulatory molecules required for T cell activation, including CD40 and B7. The latter can interact with CD28 on the surface of a CD4+ T cell. [2] [7] [8] The dendritic cell is then a fully mature professional APC. It moves from the tissue to lymph nodes, where it encounters and activates T cells. [1]

Macrophages

Macrophages can be stimulated by T cell secretion of interferon. [9] After this activation, macrophages are able to express MHC class II and co-stimulatory molecules, including the B7 complex and can present phagocytosed peptide fragments to helper T cells. [7] [8] Activation can assist pathogen-infected macrophages in clearing the infection. [10] Deriving from monocytes, a type of white blood cell, they will circulate in the blood and enter affected sites and differentiate from monocytes to macrophages. At the affected site, the macrophage surrounds the site of infection or tissue damage with its membrane in a mechanism called phagocytosis. [11]

B cells

B cells can internalize antigen that binds to their B cell receptor and present it to helper T cells. [1] Unlike T cells, B cells can recognize soluble antigen for which their B cell receptor is specific. They can then process the antigen and present peptides using MHC class II molecules. When a T helper cell with a TCR specific for that peptide binds, the B cell marker CD40 binds to CD40L on the T cell surface. When activated by a T cell, a B cell can undergo antibody isotype switching, affinity maturation, as well as formation of memory cells. [2]

Non-professional APCs

Non-professional antigen presenting cells include all nucleated cell types in the body. They use an MHC class I molecule coupled to beta-2 microglobulin to display endogenous peptides on the cell membrane. These peptides originate within the cell itself, in contrast to the exogenous antigen displayed by professional APCs using MHC class II molecules. Cytotoxic T cells are able to interact with endogenous antigen presented using an MHC class I molecule. [2] Non-professional APCs do not typically express MHC class II molecules. However, it has been observed that antigen presentation to CD4+ cells via MHC class II is not restricted to the classically professional APCs. Other leukocytes, including granulocytes such as mast cells and neutrophils, can be induced to do so, as can endothelial and epithelial cells under certain circumstances. Even so, there is little evidence that these atypical APCs are able to activate naive CD4+ T cells. [1]

Interaction with T cells

After dendritic cells have phagocytosed pathogens, they usually migrate to the vast network of lymph vessels and are carried by lymph flow to the draining lymph nodes. Each lymph node is a collection point where APCs can interact with T cells. [1] During the migration, DCs undergo a process of maturation: they lose most of their ability to further engulf pathogens and they mature by changing surface expression of MHC and co-stimulatory molecules, as well as increased production of cytokines. The internalized antigen is digested into smaller peptides containing epitopes, which are then presented to T cells by the MHC. [2] [12]

B cells reside in the lymph node. Once their B cell receptor binds to an antigen, they can interact with activated helper T cells, as described above.

A dendritic cell that interacts with an already-activated helper T cell can become licensed. [13] This occurs through the interaction of co-stimulatory molecules including B7 and CD40 on the dendritic cell, with CD28 and CD40 ligand on the T cell. Only licensed dendritic cells are able to activate cytotoxic T cells. T cell licensing of dendritic cells is key for activation of cytotoxic T cells for many pathogens, although the extent to which T cell help is needed may vary. [14]

In MHC class I and class II molecules, only certain epitopes of an internalized peptide can be presented. These epitopes are termed immunodominant. [15]

In cancer therapy

APCs naturally have a role in fighting tumors, via stimulation of B and cytotoxic T cells to respectively produce antibodies against tumor-related antigen and kill malignant cells. Dendritic cells, presenting tumor-specific antigen to T cells, are key to this process. Cancer therapies have included treating the patient with increased numbers of dendritic cells or cancer-specific T cells. However, newer therapies have turned to genetically engineered artificial antigen-presenting cells designed to prime the immune system to attack malignant cells. Some artificial APCs are derived from human cells; others are acellular, containing MHC proteins, co-stimulatory molecules and the necessary peptides. [16] [17]

The APC activator IMP321 is being tested in clinical trials to accelerate the immune reaction to eliminate metastatic breast cancer or melanoma. [18] [19]

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.

An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellular bacteria, protozoa, helminths, and fungi which could cause serious problems to the health of the host organism if not cleared from the body.

<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">Cell-mediated immunity</span> Immune response that does not involve antibodies

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 response to an antigen.

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

The adaptive immune system, also known as the acquired immune system, or specific 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 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.

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. 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 with protein antigens, for example, tumour vaccination.

Co-stimulation is a secondary signal which immune cells rely on to activate an immune response in the presence of an antigen-presenting cell. In the case of T cells, two stimuli are required to fully activate their immune response. During the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors.

<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 cell, a process known as presentation. If there has been an infection with viruses or bacteria, the 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, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, and B cells. These cells are important in initiating immune responses.

<span class="mw-page-title-main">CD80</span> Mammalian protein found in Homo sapiens

The Cluster of differentiation 80 is a B7, type I membrane protein in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is closely related to CD86, another B7 protein (B7-2), and often works in tandem. Both CD80 and CD86 interact with costimulatory receptors CD28, CTLA-4 (CD152) and the p75 neurotrophin receptor.

A tetramer assay is a procedure that uses tetrameric proteins to detect and quantify T cells that are specific for a given antigen within a blood sample. The tetramers used in the assay are made up of four major histocompatibility complex (MHC) molecules, which are found on the surface of most cells in the body. MHC molecules present peptides to T-cells as a way to communicate the presence of viruses, bacteria, cancerous mutations, or other antigens in a cell. If a T-cell's receptor matches the peptide being presented by an MHC molecule, an immune response is triggered. Thus, MHC tetramers that are bioengineered to present a specific peptide can be used to find T-cells with receptors that match that peptide. The tetramers are labeled with a fluorophore, allowing tetramer-bound T-cells to be analyzed with flow cytometry. Quantification and sorting of T-cells by flow cytometry enables researchers to investigate immune response to viral infection and vaccine administration as well as functionality of antigen-specific T-cells. Generally, if a person's immune system has encountered a pathogen, the individual will possess T cells with specificity toward some peptide on that pathogen. Hence, if a tetramer stain specific for a pathogenic peptide results in a positive signal, this may indicate that the person's immune system has encountered and built a response to that pathogen.

<span class="mw-page-title-main">HLA-DM</span>

HLA-DM is an intracellular protein involved in the mechanism of antigen presentation on antigen presenting cells (APCs) of the immune system. It does this by assisting in peptide loading of major histocompatibility complex (MHC) class II membrane-bound proteins. HLA-DM is encoded by the genes HLA-DMA and HLA-DMB.

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 prevents immune response to harmless food antigens and allergens, too.

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).

The following outline is provided as an overview of and topical guide to immunology:

Artificial antigen presenting cells (aAPCs) are engineered platforms for T-cell activation. aAPCs are used as a new technology and approach to cancer immunotherapy. Immunotherapy aims to utilize the body's own defense mechanism—the immune system—to recognize mutated cancer cells and to kill them the way the immune system would recognize and kill a virus or other micro-organisms causing infectious diseases. Antigen presenting cells are the sentinels of the immune system and patrol the body for pathogens. When they encounter foreign pathogens, the antigen presenting cells activate the T cells—“the soldiers of the immune system”— by delivering stimulatory signals that alert there is foreign material in the body with specific cell surface molecules (epitopes). aAPCs are synthetic versions of these sentinel cells and are made by attaching the specific T-cell stimulating signals to various macro and micro biocompatible surfaces like micron-sized beads. This can potentially reduce the cost while allowing control over generating large numbers of functional pathogen-specific T cells for therapy. Activated and stimulated T cells can be studied in this biomimetic contex and used for adoptive transfer as an immunotherapy.

References

  1. 1 2 3 4 5 6 7 8 9 Kambayashi T, Laufer TM (November 2014). "Atypical MHC class II-expressing antigen-presenting cells: can anything replace a dendritic cell?". Nature Reviews. Immunology. 14 (11): 719–30. doi:10.1038/nri3754. PMID   25324123. S2CID   22184839.
  2. 1 2 3 4 5 6 7 den Haan JM, Arens R, van Zelm MC (December 2014). "The activation of the adaptive immune system: cross-talk between antigen-presenting cells, T cells and B cells". Immunology Letters. 162 (2 Pt B): 103–12. doi:10.1016/j.imlet.2014.10.011. PMID   25455596.
  3. ↑ Hivroz C, Chemin K, Tourret M, Bohineust A (2012). "Crosstalk between T lymphocytes and dendritic cells". Critical Reviews in Immunology. 32 (2): 139–55. doi:10.1615/critrevimmunol.v32.i2.30. PMID   23216612.
  4. ↑ Barral DC, Brenner MB (December 2007). "CD1 antigen presentation: how it works". Nature Reviews. Immunology. 7 (12): 929–41. doi:10.1038/nri2191. PMID   18037897. S2CID   21290096.
  5. ↑ Mann ER, Li X (August 2014). "Intestinal antigen-presenting cells in mucosal immune homeostasis: crosstalk between dendritic cells, macrophages and B-cells". World Journal of Gastroenterology. 20 (29): 9653–64. doi: 10.3748/wjg.v20.i29.9653 . PMC   4123356 . PMID   25110405.
  6. ↑ Mbongue J, Nicholas D, Firek A, Langridge W (2014-04-30). "The role of dendritic cells in tissue-specific autoimmunity". Journal of Immunology Research. 2014: 857143. doi: 10.1155/2014/857143 . PMC   4022068 . PMID   24877157.
  7. 1 2 Mittal SK, Roche PA (June 2015). "Suppression of antigen presentation by IL-10". Current Opinion in Immunology. 34: 22–7. doi:10.1016/j.coi.2014.12.009. PMC   4444374 . PMID   25597442.
  8. 1 2 Brzostek J, Gascoigne NR, Rybakin V (2016-01-01). "Cell Type-Specific Regulation of Immunological Synapse Dynamics by B7 Ligand Recognition". Frontiers in Immunology. 7: 24. doi: 10.3389/fimmu.2016.00024 . PMC   4740375 . PMID   26870040.
  9. ↑ Soudja SM, Chandrabos C, Yakob E, Veenstra M, Palliser D, Lauvau G (June 2014). "Memory-T-cell-derived interferon-γ instructs potent innate cell activation for protective immunity". Immunity. 40 (6): 974–88. doi:10.1016/j.immuni.2014.05.005. PMC   4105986 . PMID   24931122.
  10. ↑ Harding CV, Boom WH (April 2010). "Regulation of antigen presentation by Mycobacterium tuberculosis: a role for Toll-like receptors". Nature Reviews. Microbiology. 8 (4): 296–307. doi:10.1038/nrmicro2321. PMC   3037727 . PMID   20234378.
  11. ↑ "Macrophages". Access Science. 2015. doi:10.1036/1097-8542.BR1109151.
  12. ↑ Dalod M, Chelbi R, Malissen B, Lawrence T (May 2014). "Dendritic cell maturation: functional specialization through signaling specificity and transcriptional programming". The EMBO Journal. 33 (10): 1104–16. doi:10.1002/embj.201488027. PMC   4193918 . PMID   24737868.
  13. ↑ Lanzavecchia A (June 1998). "Immunology. Licence to kill". Nature. 393 (6684): 413–4. Bibcode:1998Natur.393..413L. doi: 10.1038/30845 . PMID   9623994.
  14. ↑ Crispe IN (2014-01-01). "APC licensing and CD4+ T cell help in liver-stage malaria". Frontiers in Microbiology. 5: 617. doi: 10.3389/fmicb.2014.00617 . PMC   4227505 . PMID   25426113.
  15. ↑ Sadegh-Nasseri S, Chou CL, Hartman IZ, Kim A, Narayan K (June 2012). "How HLA-DM works: recognition of MHC II conformational heterogeneity". Frontiers in Bioscience. 4 (4): 1325–32. doi: 10.2741/s334 . PMID   22652874.
  16. ↑ Butler MO, Hirano N (January 2014). "Human cell-based artificial antigen-presenting cells for cancer immunotherapy". Immunological Reviews. 257 (1): 191–209. doi:10.1111/imr.12129. PMC   3869003 . PMID   24329798.
  17. ↑ Eggermont LJ, Paulis LE, Tel J, Figdor CG (September 2014). "Towards efficient cancer immunotherapy: advances in developing artificial antigen-presenting cells". Trends in Biotechnology. 32 (9): 456–65. doi:10.1016/j.tibtech.2014.06.007. PMC   4154451 . PMID   24998519.
  18. ↑ Clinical trial number NCT02676869 for "Phase 1 Study of IMP321 Adjuvant to Anti-PD-1 Therapy in Unresectable or Metastatic Melanoma" at ClinicalTrials.gov
  19. ↑ Clinical trial number NCT02614833 for "IMP321 as Adjunctive to a Standard Chemotherapy Paclitaxel Metastatic Breast Carcinoma" at ClinicalTrials.gov

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