Dendritic cells ( Latin: dendriticus = "branched") are cells of the immune system that, depending on their type, develop either from monocytes or from precursors of B and T cells . In some cases, these are only distantly related cell types, which are grouped together under the name 'dendritic cells' due to their functions.
Their function is the antigen recognition and antigen presentation previously recognized as foreign and intracellularly recorded structures such. B. Microorganisms and their components. Dendritic cells are the only cells able to induce a primary immune response by activating naive T lymphocytes. All other APCs ( antigen presenting cells ) are only able to take up, reproduce and present antigens.
By releasing appropriate cytokines and expressing certain cell surface receptors, dendritic cells influence T cells and thus strengthen the specific cellular immune defense. In accordance with the name dendritic cells, the cells first described by Ralph M. Steinman in 1973 have typical tree-like cytoplasmic runners, which give them their typical star-shaped shape. With the help of these foothills, you can effectively search larger areas for foreign antigens. In 2011, Steinman was awarded the Nobel Prize in Physiology or Medicine for this discovery .
As early as 1868 Paul Langerhans reported on a new type of cell he had discovered, the Langerhans cell later named after him . However, he wrongly assumed that this epidermal cell type is a skin nerve cell .
Dendritic cells, together with monocytes , macrophages and B-lymphocytes, belong to the so-called “professional” antigen-presenting cells of the immune system.
New research shows that dendritic cells in lymphoid tissues interact not only with T cells, but also with the other two major classes of lymphocytes, B cells and natural killer cells .
Localization in the body
Dendritic cells are found in large numbers in surface tissues of the body, such as B. Skin , pharynx (throat), upper part of the esophagus (gullet), vagina , outer cervix uteri (cervix) and anus . They are also very numerous in the inner mucous membranes , e.g. B. the respiratory and gastrointestinal systems represented. There, dendritic cells stretch their tree-like runners through the so-called tight junctions of the epithelia covering the inner and outer surfaces , without impairing the function of the covering tissue as a diffusion barrier. This expands the possibilities of the dendritic cells to receive z. B. bacterial antigens beyond their immediate environment, even if there is currently no open infection or inflammation . It is assumed that the dendritic cells thus suppress the reaction of the immune system to harmless surrounding antigens and in this way prevent an excessive immune response (see section: Function ).
After the endocytotic uptake of microbial, but also environmental and self-antigens , the dendritic cells leave the peripheral tissue in the direction of the draining secondary lymphatic organs . Pathogens that have infected peripheral sites are transported by the dendritic cells to the nearest ( lymph ) downstream lymph node ; Antigens that have got into the blood, however, are trapped in the spleen , and those that have infected mucous membranes are collected in the tonsils (tonsils) or Peyer's plaques . This process, known as cell migration (migration), is guided by regulatory signal proteins ( chemokines ) and can be intensified by vaccination . In the lymphatic organs, the places where immunity and self-tolerance are initiated, dendritic cells create a labyrinth-like intertwined system through continuous formation and deconstruction processes. There, more precisely in the paracortex of the lymph nodes (their T-cell region ), the dendritic cells present their antigens to the cells of the immune system and also release stimulating factors. Both are necessary in order to trigger an adequate immune response from the adequate, ie antigen-specific T lymphocytes .
In summary, it can be stated that dendritic cells localized in the periphery of the body absorb and process pathogens or antigens. They then migrate to the corresponding lymphatic organs, releasing lymphocyte-stimulating molecules. There they present the antigens processed into peptides using their main histocompatibility complex (MHC class II complex) so that they can be recognized by specific T lymphocytes. Through the simultaneous release of certain cytokines, the dendritic cells activate the lymphocytes and thus ultimately trigger or intensify a specific cellular immune response.
Morphology and maturation
Only immature dendritic cells of the peripheral tissue have the typical star-shaped shape, which is given to them by the long (> 10 µm ) cytoplasmic processes ( dendrites ), which can radiate in all spatial directions from the cell body . In living cells, these runners are in constant motion, they curve, are withdrawn and extended again at another point. As a result, the dendritic cells are optimally set up to intercept invading pathogens and antigens, which is why they are also referred to as “ sentinel cells ”. In this immature stage, the cells also have a large number of endocytotic vesicles that are rich in stainable lysosomal proteins. This immature phenotype is characterized by only small amounts of MHC proteins and the complete absence of costimulatory B7 molecules. During migration towards the secondary lymphatic organs, e.g. B. After antigen uptake during an infection, the morphology of the dendritic cells changes: The dendrites now give way to numerous veil-like membrane folds and protuberances, which is why the cells were originally called " veil (ed) cells ". At the same time, the cells lose the ability to phagocytose and process antigens. In the lymph nodes or other lymphatic target organs, they finally exist as mature dendritic cells. As such , they express large amounts of peptide-loaded MHC class II complexes, as well as various co-stimulatory molecules, especially B7. Both are necessary to enable the T cells to recognize and activate the processed antigens: While the peptide – MHC complexes interact with the T cell receptor, B7 molecules provide the necessary second signal by connecting Bind CD28 antigens on the T cells. The mature dendritic cells are thus able to stimulate naive CD4 + and CD8 + T cells with great efficiency. For the activation of antigen-specific, naive CD8 + T cells, contact with antigen-presenting, mature dendritic cells is sufficient. In order to enable the formation of memory cells as well as a secondary expansion of the CD8 + T cells, the dendritic cells must have been activated by CD4 + T helper cells. Simultaneous interaction of all three cell types (dendritic cells, CD4 + T helper cells and CD8 + T cells) seems to be absolutely necessary in order to transmit all costimulatory signals.
Mediator of immunity
In their role as mediators of immunity, dendritic cells have two key functions that can be clearly defined in terms of time: As immature cells, they are responsible for the uptake and processing of antigens. Only one to a few days later, as mature cells, they mainly stimulate T cells, but also B cells, by providing them with large amounts of the processed antigen in the form of MHC-peptide complexes, together with co-stimulating molecules, present on their surface. As a sentinel and alarm device for the immune system, they exercise a superordinate control function over the actual actors of the cellular immune response. Only one dendritic cell is necessary to activate 100 to 3000 antigen-specific T cells. They are thus significantly more efficient than other antigen-presenting cells, which is also due to the fact that they present 10 to 100 times more MHC-peptide complexes on their surface than z. B. monocytes or B cells.
Mediator of tolerance
The dendritic cells also play a key role in avoiding autoimmune reactions by ensuring immunological tolerance to self-antigens . As immunological watchdogs, they are incessantly collecting antigens. If there is currently no infection or inflammation in the body, these are mainly proteins from the body's own cells, which die in the context of physiological cell turnover processes . Such apoptotic cells are a steady and random source of self-antigens and are therefore critical to maintaining self-tolerance. Dendritic cells that have absorbed such endogenous antigens also migrate to the secondary lymphatic organs, where they acquire the ability to stimulate T cells. Depending on the differentiation stage of the cells, this type of stimulation does not result in an (auto) immune reaction, but in (1) apoptosis, (2) anergy or (3) the development of regulatory T cells. Each of these mechanisms helps to eliminate self-reactive T cells from the pool of peripheral lymphocytes.
Langerhans cells are found in the epidermis of the skin (especially in the stratum spinosum ) and in the mucous membranes and were named after their discoverer Paul Langerhans . Humans have around 10 9 epidermal Langerhans cells. They are not to be confused with the islets of Langerhans (which are located in the pancreas ) or the giant Langhans cells (which can be detected in granulomatous diseases of various causes). Langerhans cells arise from monocytes after stimulation with G-CSF or GM-CSF and carry the surface markers Gr-1 (synonym Ly-6G / Ly-6C) and resemble macrophages in morphology and function. These are still inactive dendritic cells. Activation and differentiation into mature dendritic cells only takes place after contact with the antigen. After antigens have been absorbed via phagocytosis, they migrate to the regional lymph nodes . Dendritic cells present antigens, especially the T lymphocytes. The detection of so-called Birbeck granules in electron microscopy is characteristic of dendritic cells . These are tennis racket-shaped cytoplasmic formations with a partially pentalaminal structure in the area of the handle. Histologically , dendritic cells show a typically notched nucleus and a very dark cytoplasm. Langerhans cells express Langerin , with which HIV particles can be bound.
Interdigitating dendritic cells
The interdigitating dendritic cells come from the bone marrow . They are found throughout the body, but especially in the T-cell regions of the lymph nodes , in the periarteriolar lymphocyte sheath of the spleen , in the thymus , tonsils and Peyer's plaques . The plasma membrane is ATPase positive. They are the most effective antigen-presenting cells for naive T cells and are particularly important for the presentation of viral antigens. Histologically they show typical folds of the plasma membrane and a bizarre cell nucleus . The interdigitating dendritic cells show no Birbeck granules under the electron microscope . Processed antigens are presented to CD4 -positive T lymphocytes via MHC2 molecules . The release of cytokines by the dendritic cells leads to the stimulation and proliferation of T lymphocytes. This cell type has the costimulatory molecules B7-1 and B7-2 on the plasma membrane. Interdigitating dendritic cells are the most potent stimulators for naive T lymphocytes. Mature cells but also antigen-presenting cells no longer show any phagocytic activity.
Interstitial dendritic cells
Interstitial dendritic cells are of myeloid origin and were isolated for the first time from the interstitial space ( interstitium ) of non-lymphoid organs as leukocytes with high MHCII expression. So far, IDC have been detected in mammals, they play a role in the initiation of the rejection reaction against allogeneic transplants .
Inflammatory dendritic cells
Inflammatory dendritic cells (inflDC) arise in acute inflammation or infection and in chronic inflammatory diseases. They are absent in healthy, non-inflamed tissue. InflDC develop from monocytes that migrate from the blood into the inflamed tissue and there take on the properties of dendritic cells. Two features clearly characterize them as DC and not as macrophages: InflDC migrate from the tissue into the draining lymphatic organs, and they efficiently present antigen and thus activate naive CD4 and CD8 T cells.
Plasmacytoid dendritic cells
Plasmacytoid dendritic cells (pDC) are a relatively rare type of dendritic cells found in the blood and peripheral lymphatic organs. They express the surface markers CD123 , CLEC4C and BDCA-4 , but neither CD11c nor CD14 , which are respectively characteristic of dendritic cells and monocytes. As part of the innate immune system, they express the toll-like receptors TLR-7 and TLR-9 . After activation, pDCs release large amounts of Type I interferons (IFN-α and IFN-β). The number of circulating pDCs decreases during HIV or HCV infection.
Follicular dendritic cells
Follicular dendritic cells (fDC) are found in primary and secondary follicles of lymph follicles (e.g. in lymph nodes, Peyer's plaques, spleen). They show strong and fine branching from long dendrites and are connected to neighboring cells via desmosomes and gap junction proteins. Follicular dendritic cells should not be confused with conventional dendritic cells because they are not able to take up, process and present antigens via MHCII. In addition, they are negative for hematopoietic cell line markers. Follicular dendritic cells are long-lived, radio-resistant, and are of mesenchymal origin. Characteristic of follicular dendritic cells is the presentation of unprocessed antigen via antigen- antibody complexes on Fc receptors or complement- antigen complexes on the complement receptor CD21 / 35 (CR1 / 2). Follicular dendritic cells secrete cytokines that are important for the homeostasis, activation, differentiation, and proliferation of B lymphocytes .
Dendritic cells can be used to vaccinate against existing cancerous tumors . Here, isolated dendritic cells are loaded with tumor antigens , stimulated with cytokines and infused back into the patient. The dendritic cells are supposed to show the immune system the tumor that is already present in the body, but mostly not recognized or not fought by the immune system, and thus “incite” the immune defense against the tumor. This cancer vaccination with dendritic cells, a form of cancer immunotherapy , is slowly beginning to establish itself as a form of therapy. In April 2010, such a vaccine for the treatment of prostate cancer was approved by the FDA for the first time in the USA. By then, several studies with a total of more than 4500 patients who received treatment with dendritic cells had been published, the lion's share of them in Europe and the USA. The majority of the dendritic cells used were generated from the patient's own monocytes as precursor cells (this is the most frequently used cultivation method); more rarely, the cells are grown from proliferating CD34 + cells or collected directly from the blood (but only in very small numbers). Among the patient groups treated so far, melanoma predominates with almost 1400 published cases, followed by urological tumors (prostate and renal cell carcinoma) with approx. 900 patients as well as tumors of the digestive system, the brain, the female breast, lung carcinoma and hematological diseases. To load the dendritic cells, tumor recognition components (tumor antigens) are loaded onto the cells, either by loading short protein sequences ( peptides ) onto the cells, or by loading the information for these protein sequences in the form of RNA , DNA or even the whole protein Cells loads. In this way, even the customized information of a patient's own tumor can be transferred to the dendritic cells, for example by extracting the RNA from a tumor and placing this information in the dendritic cells of this patient. Therapy with dendritic cells has so far mostly been used in patients with a large tumor burden. This therapy also leads to regression of existing tumors. Much more common, however, is a stabilization of the disease followed by a slow transformation of the tumors into scar-like tissue. The side effects of the therapy are mostly expressed as local reactions at the puncture sites and as tiredness, sometimes combined with a rise in temperature. These reactions indicate a response to the vaccine and are assessed as what is known as reactogenicity. Langerhans cells play a major role in type IV hypersensitivity reactions (cellular immune reaction of the delayed type). This is the case , for example, with contact eczema.
The role of Langerhans cells in HIV - infection experienced a different rating by one study. While it was previously assumed that Langerhans cells carry the virus from the mucous membranes of the genital tract into the regional lymph nodes with a subsequent infection of lymphocytes and the progression of the infection, this fact is now seen in a more differentiated manner. The Langerhans cells identify the HI virus via the Langerin recognition molecule and bind it to themselves, but place it in a specific cell area where it is “disarmed” and broken down. These new findings from the research team led by T. Geijtenbeek are in opposition to the previous view that dendritic cells are an important reservoir for the HI virus. According to these findings, the latter scenario should only occur if high amounts of virus occur or if there are injuries that allow the viruses to penetrate deeper layers of the skin that are not penetrated by the protective molecule Langerin.
Therapy with dendritic cells is also used in veterinary medicine. The treatment concept is based on the already known procedure from human medicine. Dogs, cats and horses suffering from tumors are treated as a rule. The dendritic cells are cultivated from a blood sample and placed in an injection solution (also called a vaccine). The vaccine is administered intradermally to the animal. The aim of the treatment is to improve the body's own immune response and thus to combat tumor cells using the immune cells. The antigens taken up by the dendritic cells are presented to the T cells so that the T cells are reactivated. The immune cells thus begin to destroy degenerate cells.
Dendritic cell therapy can be used on its own or as an adjunct therapy before or after chemotherapy or radiation therapy. Dendritic cells are typically used after the surgical removal of the tumor tissue to combat allegedly remaining tumor cells or to effectively prevent a relapse. Inoperable tumors can be inhibited in their growth with the help of dendritic cells.
- K. Palucka, J. Banchereau: Cancer immunotherapy via dendritic cells. In: Nature Reviews Cancer . Volume 12, Number 4, April 2012, pp. 265-277, ISSN 1474-1768 . doi: 10.1038 / nrc3258 . PMID 22437871 . PMC 3433802 (free full text). (Review).
- K. Palucka, H. Ueno and others: Dendritic cells and immunity against cancer. In: Journal of internal medicine. Volume 269, Number 1, January 2011, pp. 64-73, ISSN 1365-2796 . doi: 10.1111 / j.1365-2796.2010.02317.x . PMID 21158979 . PMC 3023888 (free full text). (Review).
- AK Palucka, H. Ueno and others: Taming cancer by inducing immunity via dendritic cells. In: Immunological Reviews . Volume 220, December 2007, pp. 129-150, ISSN 0105-2896 . doi: 10.1111 / j.1600-065X.2007.00575.x . PMID 17979844 . (Review).
- ↑ RM Steinman, ZA Cohn: Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. In: The Journal of experimental medicine. Volume 137, Number 5, May 1973, pp. 1142-1162, ISSN 0022-1007 . PMID 4573839 . PMC 2139237 (free full text).
- ↑ P. Langerhans: About the nerves of the human skin. In: Virchow's archive. Volume 44, Berlin 1868, pp. 325-337.
- ↑ M. Lucas, W. Schachterle, K. Oberle, P. Aichele, A. Diefenbach: Dendritic cells prime natural killer cells by trans-presenting interleukin 15. In: Immunity. Volume 26, Number 4, April 2007, ISSN 1074-7613 , pp. 503-517, doi: 10.1016 / j.immuni.2007.03.006 . PMID 17398124 , PMC 2084390 (free full text).
- ↑ a b G. J. Randolph, V. Angeli, MA Swartz: Dendritic cell trafficking to lymph nodes through lymphatic vessels. In: Nature reviews. Immunology. Volume 5, Number 8, August 2005, ISSN 1474-1733 , pp. 617-628, doi: 10.1038 / nri1670 . PMID 16056255
- ↑ M. Rescigno, M. Urbano, B. Valzasina, M. Francolini, G. Rotta, R. Bonasio, F. Granucci, JP Kraehenbuhl, P. Ricciardi-Castagnoli: Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. In: Nature Immunology . Volume 2, Number 4, April 2001, ISSN 1529-2908 , pp. 361-367, doi: 10.1038 / 86373 . PMID 11276208 .
- ↑ JG Cyster: Chemokines and the homing of dendritic cells to the T cell areas of lymphoid organs. In: The Journal of experimental medicine. Volume 189, Number 3, February 1999, ISSN 0022-1007 , pp. 447-450. PMID 9927506 , PMC 2192905 (free full text).
- ↑ P. Bousso, E. Robey: Dynamics of CD8 + T cell priming by dendritic cells in intact lymph nodes. In: Nature Immunology . Volume 4, Number 6, June 2003, ISSN 1529-2908 , pp. 579-585, doi: 10.1038 / ni928 . PMID 12730692 .
- ↑ G. Shakhar, RL Lindquist, D. Skokos, D. Dudziak, JH Huang, MC Nussenzweig, ML Dustin: Stable T cell-dendritic cell interactions precede the development of both tolerance and immunity in vivo. In: Nature Immunology . Volume 6, Number 7, July 2005, ISSN 1529-2908 , pp. 707-714, doi: 10.1038 / ni1210 . PMID 15924144 , PMC 1560107 (free full text).
- ↑ E.-J. Speckmann ao: Physiology . 5th edition. Verlag Urban & Fischer, Elsevier, Munich 2008, ISBN 978-3-437-41318-6 , p. 382.
- ↑ a b c d J. Banchereau, RM Steinman: Dendritic cells and the control of immunity. In: Nature. Volume 392, number 6673, March 1998, ISSN 0028-0836 , pp. 245-252, doi: 10.1038 / 32588 . PMID 9521319 .
- ↑ SC Knight, BM Balfour, J. O'Brien, L. Buttifant, T. Sumerska, J. Clarke: Role of veiled cells in lymphocyte activation. In: European Journal of Immunology. Volume 12, Number 12, December 1982, ISSN 0014-2980 , pp. 1057-1060, doi: 10.1002 / eji.1830121214 . PMID 7160425 .
- ↑ SC Knight: Veiled cells- "dendritic cells" of the peripheral lymph. In: Immunobiology. Volume 168, Number 3-5, December 1984, ISSN 0171-2985 , pp. 349-361, doi: 10.1016 / S0171-2985 (84) 80122-9 . PMID 6241604
- ↑ K. Balakrishnan, LE Adams: The role of the lymphocyte in an immune response. In: Immunological investigations. Volume 24, Numbers 1-2, Jan-Feb 1995, ISSN 0882-0139 , pp. 233-244. PMID 7713585 .
- ↑ Charles A. Janeway Jr. et al .: Immunobiology: the immune system in health and disease , from it in particular: 8-6: Dendritic cells specialize in taking up antigen and activating naive T cells & Figure 8.2: Immature dendritic cells take up antigen in the tissues , 5th edition. Garland Publishing, New York 2001, ISBN 0-8153-3642-X .
- ^ CM Smith: Cognate CD4 (+) T cell licensing of dendritic cells in CD8 (+) T cell immunity. In: Nat Immunol. 5 (11), Nov 2004, pp. 1143-1148. Epub 2004 Oct 10.
- ↑ S. Hoyer et al .: Concurrent interaction of DCs with CD4 (+) and CD8 (+) T cells improves secondary CTL expansion: It takes three to tango. In: Eur J Immunol. 44 (12), Dec 2014, pp. 3543-3559. doi: 10.1002 / eji.201444477 . Epub 2014 Oct 27.
- ^ JK Tan, HC O'Neill: Maturation requirements for dendritic cells in T cell stimulation leading to tolerance versus immunity. In: Journal of leukocyte biology. Volume 78, Number 2, August 2005, ISSN 0741-5400 , pp. 319-324, doi: 10.1189 / jlb.1104664 . PMID 15809288 .
- ^ DN Hart, JL McKenzie: Interstitial dendritic cells. In: International reviews of immunology. Volume 6, Numbers 2-3, 1990, pp. 127-138, ISSN 0883-0185 . PMID 2152498 . (Review).
- ↑ E. Segura, S. Amigorena: Inflammatory dendritic cells in mice and humans. In: Trends in immunology. Volume 34, Number 9, September 2013, ISSN 1471-4981 , pp. 440-445, doi: 10.1016 / j.it.2013.06.001 . PMID 23831267 .
- ↑ AL Harzstark, EJ Small: Immunotherapy for prostate cancer using antigen-loaded antigen-presenting cells: APC8015 (Provenge). In: Expert opinion on biological therapy. Volume 7, Number 8, August 2007, pp. 1275-1280, ISSN 1744-7682 . doi: 10.1517 / 147125220.127.116.115 . PMID 17696825 . (Review).
- ↑ C. Larkin: Dendreon Rises After Winning Approval for Cancer Drug (Update2). In: Businessweek.com , April 29, 2010.
- ^ L. de Witte, A. Nabatov, M. Pion, D. Fluitsma, MA de Jong, T. de Gruijl, V. Piguet, Y. van Kooyk, TB Geijtenbeek: Langerin is a natural barrier to HIV-1 transmission by Langerhans cells. In: Nature medicine. Volume 13, Number 3, March 2007, pp. 367-371, ISSN 1078-8956 . doi: 10.1038 / nm1541 . PMID 17334373 .
- ↑ Simon Grammel: The treatment method with dendritic cells. PetBioCell, accessed October 18, 2018 .
- ↑ Thomas Grammel: Dendritic cells in cancer therapy. Retrieved October 18, 2018 .