Antigen-presenting cell

An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen complexed with major histocompatibility complexes (MHCs) on their surfaces; 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.

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

Almost all cell types can present antigens in some way. They are found in a variety of tissue types. Professional 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

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 a monocyte, type of white blood cell, they will circulate 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

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 [18]

[19] to accelerate the immune reaction to eliminate metastatic breast cancer or melanoma.

References
  1. 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.
  2. 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.
  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. 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. 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. 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

Further reading
  • Kindt TJ, Goldsby RA | title = Kuby immunology | edition = 6th edition | publisher = W.H. Freeman | date = 2007 }}
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