DC cells were first isolated from the spleen by Steiman and Cohn in 1973. They are a type of white blood cells that are different in shape and function from granulocytes, macrophages and lymphocytes. Because their cell membranes protrude outward, they form The membranous dendritic processes are similar to the axons of nerve cells, so they are named dendritic cells.
DC cell diagram (dendritic cells, DCs). It is the most powerful professional antigen-presenting cell (APC) in the body. It can efficiently absorb, process and present antigens. Immature DCs have strong migration ability, and mature DCs can effectively activate naive DCs. T cells are at the center of initiating, regulating, and maintaining immune responses.
DCs are closely related to the occurrence and development of tumors. The greater the number of DCs infiltrating in most solid tumors, the better the prognosis of the patient. The core of an effective anti-tumor immune response is to generate a cellular immune response dominated by CD8+ T cells, which is also the basis of DC as an immunotherapy method.
Elie Gilbois, director of research at the Center for Genetics and Cell Therapeutics at Duke University, said: "DC is one of the most effective ways to stimulate the body's immune system to resist cancer invasion." "DC As a highly specialized primary antigen-presenting cell, it plays a key role in inducing efficient and specific T cell immune responses against relevant antigens. ”
Source
Human dendrites. Like cells originate from hematopoietic stem cells (hemopoietic stem cells). There are two sources of DC:
① Myeloid stem cells differentiate into DC under the stimulation of GM-CSF, called myeloid dendritic cells (MDC), also known as DCl, and monocyte Cells and granulocytes have the same precursor cells; including Langerhans cells (LCs), mesothelial (or dermal) DCs, and monocyte-derived DCs.
② Derived from lymphoid stem cells, called lymphoid DC (Lymophoid dendritic cells, LDC) or plasmacytoid dendritic cells (piX;), that is, DC2, which is related to T cells and NK cells. ***Different precursor cells. Although the number of dendritic cells (DC) is less than 1% of peripheral blood mononuclear cells, their surface is rich in antigen-presenting molecules (MHC-Ⅰ and MHC-Ⅱ), cytokine-stimulating factors (CD80/B7-1, CD86/B7-2, CD40, CD40L, etc.) and adhesion factors (ICAM-1, ICAM-2, ICAM-3, LFA-1, LFA-3, etc.), are powerful professional antigen-presenting cells (APCs) .
DC itself has immune stimulating ability and is the only APC that can activate unsensitized initial T cells.
The cross-organ operation of DC cells in the human immune mechanism.
Knowledge system
1. Definition and function of Dendritic Cell:
1) Dendritic cells (DCs) are a special type of antigen-presenting cells. Found in most organizations.
2) Dendritic cells (DCs) have the role of initiating immune mechanisms, including responses to many different pathogens, and link the innate response to pathogens to the development of adaptive immunity.
3) Dendritic cells (DCs) can also mediate immune tolerance or immune silencing, which is necessary to prevent unnecessary immune responses to self and environmental antigens.
2. Source of Dendritic Cell (subgroup/subset): ****The five main types of DCs.
1) plasmacytoid DCs (PDCs):
Plasma DCs produce large amounts of type I IFN (interferon) through the nucleic acid sensors Toll-like receptor 7 (TLR7) and TLR9 in response to Virus.
2) Classic or tissue-resident DCs (cDCs):
Classic or tissue-resident DCs are found in lymphocytes, such as spleen and lymph nodes.
3) Migratory DCs:
Migratory DCs, found in non-lymphoid organs (such as skin, lungs and intestines), migrate dendritic cells to sample the surrounding environment, and then Migrate to draining lymph nodes and act as sentinels, providing tissue-derived antigens to T cells to induce immunity or tolerance.
4) Monocyte-derived DCs (Mo-DCs):
Monocyte-derived DCs are dendritic cells transformed from monocytes.
5) Langerhans cells (LS):
Langerhans cells are found in lamellar squamous epithelium, such as skin and similar epithelium on the surface of the oral cavity and genitals.
Different subsets of DCs have different intrinsic properties. This means that each subset can quantitatively or qualitatively express specific surface receptors, specifically lectins involved in antigen uptake and presentation, signaling receptors (specific toll-like receptors), cytokines/chemokines, etc.
All subpopulations can link innate and adaptive immunity, but more research is needed to determine whether different subpopulations can induce different forms of tolerance.
3. Dendritic Cell characteristics and markers
1) Classic DC-restricted precursors (preDC) and PDC come from the same DC progenitor (CDP) in the bone marrow, It has lost its potential to form monocytes. After leaving the bone marrow, preDCs and PDC circulate through the blood to lymphoid organs (such as the spleen and lymph nodes).
2) In the murine blood system (BLOOD), preDCs express low levels of major histocompatibility complex II (MHC II) and differentiate into classical DC or tissue-resident CD8α+ and CD8α at a late stage ?DCs.
3) There are two types of dendritic cells expressing high MHCII in human blood: BDCA-1/CD1c+ and BDCA-3/CD141+.
(BDCA: blood dendritic cell antigen, blood dendritic cell antigen.)
4) In skin-draining lymph nodes (SKIN DRAINING LN), Mo-DCs have High ability to present antigen to CD4+ and CD8+ T cells. Under steady state, Mo-DCs are rarely found in skin-draining lymph nodes, but this subset of cells increases significantly after stimulation with TLR4 agonists, such as lipopolysaccharide (LPS).
5) In the skin system (SKIN), CD103+ epidermal LCs (epidermal Langerhans cells, LCs) and dermal dendritic cells (dermal DCs) can express the lectin Langerin and migrate to skin drainage lymph nodes. Epidermal LCs are originally derived from progenitor cells in the fetal liver or yolk sac and are dependent on macrophage colony-stimulating factor (M-CSF). Once LCs enter the epidermis, they become radiation resistant.
6) In contrast, CD103+ dermal dendritic cells are derived from blood preDCs, which are dependent on FSM-like tyrosine kinase 3 ligand (FLT-3L) and are sensitive to radiation. In the dermis, CD103+CD11b- and CD103?CD11b+ dermal DCs can be further subdivided into other subsets using additional markers.
(Other LC markers include epithelial cell adhesion molecule (EpCAM), F4/80, E-cadherin, and CD11b. Both LCs and CD103+ dermal DCs express DEC-205/CD205.)
7) CD8α+ Both cDCs and CD103+ CD11b?migratory DCs are dependent on the transcription factors basic leucine zipper transcription factor ATF-like 3 (Batf3), DNA binding inhibitor 2 (Id2) and interferon regulatory factor 8 (IRF8). Furthermore, CD8α+ cDC and CD103+ DC showed excellent ability to cross-present antigens and prime CD8+ T cells.
8) On the other hand, although there are currently fewer markers to identify DC subsets, known studies have found that CD8α-cDC is similar to CD103-CD11b +migratory DC. cDCs in lymphoid organs express more CD11c and less MHC II than migratory DCs from other tissues, such as lung, skin, and intestine.
9) In the spleen (SPLEEN), CD8α+ cDCs selectively capture dead cells from the blood stream through receptor ligand contact pattern recognition, including CD36, αvβ5, Treml4 ( triggering receptor expressed on myeloid cells -like 4), CLEC9A or DNGR1 and CLEC12A. The major hallmark of CD8αα is the DC subset of lymphoid organs in mice, but not in other species.
10) In the intestine (INTESTINE), a subset of migratory DCs is reported to be located in the center of the villus nucleus of the intestinal lamina propria and express both CD11b and CD103.
11) CD103+ CD11b+ and CD103+ CD11b? intestinal DC subpopulations are both derived from preDCs, which migrate to mesenteric lymph nodes in a C-C chemokine receptor type 7 (CCR7)-dependent manner.
12) CX3CR1high CD11c+ MHC II+ cells express multiple tissue macrophage markers, including F4/80, which are selectively inhibited when the M-CSF receptor is disrupted in mice With reduced expression, this cell population can extend processes between columnar epithelial cells into the intestinal lumen to sample antigen, but in steady state is unable to migrate to lymph nodes.
13) The epithelial cells on Peyer's patch and other lymphoid organs associated with the mucosa have a special type of epithelial cells called M cells, or microfold cells. M cells transport antigens to underlying tissues, where they are then taken up by local DCs. Dendritic cells receive antigens via M cells, then migrate to visceral-associated lymphoid tissue (GALT) and present them to T cells.
14) In the mediastinal/mesenteric LN, small intestinal CD103 + DC (14) produce the vitamin A metabolite retinoic acid (RA), which synergizes with TGF-β to promote Foxp3 + Differentiation of regulatory T cells (Treg). In addition, RA also induces the expression of homing receptors CCR9 and α4β7 on T cells.
15) In the skin, ultraviolet B (UBV) radiation in the skin also promotes tissue homing of T cells, similar to dietary sources of vitamin A (RA) in the gut. Vitamin D3 produced locally by UVB in the skin can be metabolized by DCs to its active compound 1,23(OH)2D3, thereby inducing the upregulation of CCR10 in T cells and directed transfer to the skin.
16) In lung tissue, the airways are lined with CD103+ endoepithelial DCs, which can sample antigens from the airway lumen by extending their dendrites between epithelial cells.
Characteristics of DC cells stimulating immune response
Treatment process
1. Extract 50-60ml of the patient's peripheral blood - isolate mononuclear cells and induce DC cells in vitro ——DC cells loaded with tumor antigens are infused back to the patient intravenously or injected subcutaneously. DCs loaded with tumor antigens can stimulate autologous T cells to produce a strong anti-tumor immune response.
2. Extract 200ml of the patient's peripheral blood - isolate mononuclear cells and induce DC cells in vitro - DC cells are loaded with tumor antigens and mixed with autologous lymphocytes to stimulate autologous T cells to produce cytotoxic T lymphocytes - These cytotoxic T lymphocytes are injected back into the patient through subcutaneous injection - directly killing tumor cells.
Mechanism of immune effect of DC cells
DC cells are the most powerful professional antigen-presenting cells known in the body and the only ones that can activate resting T cells. They are responsible for initiating, regulating and maintaining immunity. The central part of the response. Through a large number of in vitro activation and culture of DC cells loaded with tumor antigens, when the number of cells reaches a certain number and then infused back to the patient, the body can be induced to produce a strong anti-tumor immune response.
DC is an important component of tumor cell immunotherapy. DC cell vaccines have great flexibility in operation, including the source of DC cells, isolation methods, antigen introduction methods, extending survival time, improving activity, etc. There are many different operating methods, each method has its own advantages. , therefore a variety of treatment methods can be derived through different optimization and combinations to adapt to patients with different conditions. A large number of studies have shown that DC vaccines are safe, easy to operate, have immunosuppressive effects on a range of types of tumors, and have achieved encouraging preliminary results in tumor immunotherapy.
The mechanism of action of DC cells in treating tumors
In tumor immunity, DC cannot directly kill tumor cells, but they can recognize tumor cell-specific antigens and present their signals to killer cells. Effector T cells to achieve the functions of monitoring and killing tumors.