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NK cell biological characteristics

NK cells are important players in the innate immune system and constitute the first line of defense against cancer cells. Natural killer (NK) cells were defined by Herberman in 1976 as a new lymphocyte population. NK cells are distributed throughout the body, accounting for 5-20% of all lymphocytes in the blood and organs. Due to the presence of unique chemokine receptors, NK cells are distributed differently in healthy tissues, in the bone marrow, spleen, liver, lungs, skin The concentration is higher in , kidney, uterus and secondary lymphoid tissue. NK cells are derived from CD34+ common lymphoid progenitor cells and differentiate into immature and mature NK cells in the bone marrow (BM). It then distributes to lymphoid and nonlymphoid peripheral organs and tissues, including PB, spleen, lungs, liver, and uterus.

The development process of NK cells

NK cells have cytotoxic capabilities similar to CD8+ T cells that play a role in adaptive immunity but lack CD3 and T cell receptors (TCR). NK cells mainly circulate in the blood, accounting for approximately 5-10% of peripheral blood mononuclear cells (PBMC), and are present in lymphoid tissues such as bone marrow and spleen. Similar to other ILCs, NK cells originate from common lymphoid progenitor (CLP) cells in the bone marrow (Figure 1), with an average renewal period of approximately 2 weeks.

During development, a process called “education” describes the interaction of NK cells expressing the immunoreceptor tyrosine inhibitory motif (ITIM) with major histocompatibility complex-I (MHC-I), Helps NK cells gain permission and avoid attacking healthy normal cells. Interestingly, tumor cells always lack or express only low levels of MHC-I to escape CD8+ T cell-mediated cytotoxicity, whereas licensed NK cells are fully activated. However, tumor cells also express molecules that activate NK cells, such as MHC class I peptide-related sequence A (MICA) and MICB, supporting the use of NK cells as anticancer agents. In addition, unlicensed NK cells also play important roles in the body, such as eliminating murine cytomegalovirus (MCMV) infection and MHC-I+ cells.

To date, NK cell survival and development are thought to depend mainly on cytokines (especially IL-2 and IL-15) and transcription factors (Nfil3, Id2, and Tox for development, and EOMES and T-bet for maturation). GRB2-associated binding protein 3 (GAB3) is essential for IL-2 and IL-15 mediation, and its deficiency results in impaired NK cell expansion. Furthermore, targeting relevant signals is a potential option to promote NK cell-induced cancer cytotoxicity. As mentioned previously, ablation of cytokine-inducible SH2-containing protein (CIS), which negatively regulates IL-15 to limit NK cell function, prevents metastasis and enhances CTLA-4 and PD-1 blockade therapy in vivo.

NK cell surface molecules

Due to the variable expression of NK cell surface markers, it is difficult to accurately identify this cell type and, more importantly, their functional status using one or two simple molecules or traditional immunohistochemistry. However, in human clinical and research settings, CD3-CD56+ cells are generally considered NK cells and can be further divided into CD56bright and CD56dim subpopulations. CD56 is not only a marker but also plays an important role in the terminal differentiation of NK cells, as its blockade by monoclonal antibodies significantly inhibits the transition from CD56bright to CD56dim, thereby limiting the cytotoxic capacity.

Consistently, CD3-NK1.1+ and CD3-CD49b+ cells were defined as NK cells in mice. In recent studies, based on the consensus of adding more functional proteins rather than surface molecules to the classification, it was proposed that natural cytotoxic receptor 46 (NKp46), which belongs to the natural cytotoxic receptors (NCR), should also be included in this Conceptual NK cell system in panel.

Activating and inhibitory signals in NK cells

As the main effector cell type in innate immunity, NK cells are able to kill tumor cells and virus-infected cells at a very early stage. Lacking abundantly produced receptors to specifically distinguish the incalculable number of antigens in the body, they rely on “missing self” and “induced self” modes to recognize target cells by maintaining a precise balance between activating costimulation and inhibition. Signaling (mainly through functional receptors). These interacting signals ultimately determine the activation and functional status of NK cells.

Activating signals include cytokine-binding receptors, integrins, killer receptors (CD16, NKp40, NKp30, and NKp44), receptors that recognize non-self antigens (Ly49H), and other receptors (e.g., NKp80, SLAM, CD18, CD2, and TLR3/9). In general, NK cell activating receptors can be divided into at least three types according to their respective ligands, including MHC-I specific receptors, MHC-I related receptors, and MHC-I non-related receptors (Table 1 ).

It should be emphasized that NCRs belonging to the third group include three molecules (NKp30, NKp44, and NKp46), and NKp30 has been shown to recognize B7-H6 expressed on tumor cells and can be used as a new therapeutic option in the future.

NK cell surface receptors and ligands on tumor cells are involved in tumor recognition. NK cells express a set of stimulatory (or activating) and inhibitory receptors and recognize healthy cells and abnormal cells, such as viral infections or potentially tumorigenic cells, through the appearance of MHC-1 receptors.

Modulation of natural killer (NK) cell responses according to the “missing self” and “altered self” models. ((A) The presence of major histocompatibility complex (MHC)-I as an inhibitory NK cell receptor ligand, and the lack of stress-induced ligands on the surface of healthy cells, results in a dominant inhibitory signal to NK cells.( B) The presence of stress-inducing ligands that activate NK cell receptors and downregulation of MHC-I by tumor cells results in the primary activation signal for NK cells. [Color figure can be viewed at]

Inhibitory signals mainly include receptors that recognize MHC-I, such as Ly49s, NKG2A, and LLT1, as well as some receptors unrelated to MHC-I (Table 1). In addition, MHC-I-specific inhibitory receptors can generally be divided into three types based on structure and function: killer cell immunoglobulin-like receptors (KIRs), killer lectin-like receptors (KLRs), and leukocyte immunoglobulins like receptor (LILR).

NK cell subpopulations according to mature site

Conventional NK (cNK) cells mainly exist in peripheral blood and migrate to specific locations to function. NK cells also include tissue-resident NK (trNK) cells. The complex process of NK cell differentiation occurs in several different tissues, including bone marrow, liver, thymus, spleen, and lymph nodes, and may involve cell cycling at different stages of maturation between these tissues. In bone marrow, blood, spleen, and lungs, NK cells are fully differentiated, whereas in lymph nodes and intestines, NK cells are immature and progenitor. Single-cell transcriptome analysis of bone marrow and blood NK cells helps elucidate their characteristic changes during development. For example, high expression of TIM-3, CX3CR1 and ZEB2 represents a more mature state.

In summary, NK cells in various tissues have different characteristics, have different functions and form close relationships with other stromal cells. In the lung, trNK cells display a distinct phenotype from circulating NK cells (mainly CD56dim) and are thought to express varying levels of CD16, CD49a, and CD69, with CD56dimCD16+ cells representing the majority of the entire NK family. Notably, CD69+ cells are the predominant type of CD56brightCD16-NK cells. However, in the thymus, the majority of NK cells are CD56highCD16-CD127+, which are highly dependent on GATA3 compared with the CD56+CD16+ subset. In addition, they produce more effector molecules, including TNF-α and IFN-γ.

Similarly, hepatic trNK cells can be divided into two groups, including CD56brightCD16+/- and CD56dimCD16+, both lacking CD3 and CD19. In addition, CD49a+CD56+CD3-CD19-NK cells have been identified in liver biopsies. In addition, hepatic NK cells can generate memory for structurally diverse antigens, depending on the surface molecule CXCR6. In the uterus, the majority of NK cells are CD56brightCD16- and express high levels of KIR. For skin NK cells, it is interesting that only very few CD56+CD16+, which are commonly found in peripheral blood, can be detected. Interestingly, trNK cells differ between subcutaneous (CD56dim) and visceral (CD56bright) adipose tissue and can generally be divided into three groups based on CD49b and Eomes, showing different CD49a (CD49b+ Eomes- subgroup) and CD69 expression levels (CD49b-Eomes+ subgroup).

NK cell subpopulations classified according to functional molecules

Based on the expression of surface CD56, NK cells can be divided into CD56bright and CD56dim. CD56dim NK cells mainly exist in peripheral blood and are always CD16 positive, express high levels of KIR and LFA-1, and display cell killing ability.

CD16 is a key receptor that mediates antibody-dependent cellular cytotoxicity (ADCC) and induces immunoreceptor tyrosine activation motif (ITAM) phosphorylation. Based on time-resolved single-cell assays, NK cell cytotoxicity was inhibited through necrosis and apoptosis. Therefore, FasL/FasR interaction, forin/granzyme release, and Ca2+ influx are all important for NK cell function. However, CD56bright NK cells are similar to helper cells and mainly secrete cytokines such as IFN-γ, TNF-β, and GM-CSF. The researchers even further divided these cells into NK1 and NK2 categories, consistent with Th1 and Th2, which primarily secrete IFN-γ and IL-5, respectively.

In addition to the established cytotoxic cNK cells, NK cells have been shown to differentiate into antigen-presenting NK (AP-NK) cells, helper NK (NKh) cells, and regulatory NK (NKreg) cells, each defined by surface molecules and individual functions. A new CD8αα+ MHC-II+ phenotype with professional APC capabilities is thought to represent unusual AP-NK cells, recognizing and eliminating autoreactive T cells and ultimately killing them like cNK cells. Human plasmacytoid dendritic cells (DC) activated by the prophylactic vaccine FSME upregulated the expression of CD56 on their surface.

Invariant natural killer T cells (iNKT) constitute a subset of T cells that express NK cell markers. NKT is activated by antigen presented by CD1d and can not only secrete Th1-type cytokines, but also secrete Th2-type cytokines to participate in immunity. Th1-polarized iNKT cells exhibit a tumor-depleting phenotype, whereas Th2-polarized iNKT cells resemble polarized T cells and contribute to tumor progression. Recent studies have also highlighted new functional subtypes of iNKT cells. However, in recent years, due to their close relationship with innate immunity, iNKT cells have been potentially defined as a special subset of ILCs.

As seen from the development and function of NK cells, they play different roles in cancer biology. NK cells exert anti-tumor immunity through interactions with cancer cells, stromal cells, extracellular matrix, especially metabolites.

Different ways of NK cell-mediated tumor killing and immune system regulation: (A) NK cells can enhance antigen presentation to T cells by killing immature DCs while promoting IFN-γ and TNF-α-mediated DC maturation Presentation. (B) NK cells can specifically recognize cells that lack expression of their own MHC class I molecules (Missing-self). (C) ADCC can kill target cells. (D) The Fas/FasL pathway is a very efficient NK cell-mediated cell killing (E) The cytokine pathway can exert anti-tumor potential because cytokines (such as NK cells) secrete a variety of cytokines such as TNF- α. (F) The NK cell receptor NKG2D recognizes “inducible self” ligands that are expressed at very high rates in response to activation of tumor-related pathways. (G) Checkpoint blockade can inhibit NK cell inhibition by preventing the interaction of N cell inhibitory receptors with their ligands. (H) As a result of adoptive NK cell transfer, mismatch between donor and recipient, inhibitory KIR, NK cells eliminate allogeneic tumor cells lacking their own MHC. (I) CAR-NK cells specifically designed to target overexpressed tumor antigens can also be used to eliminate specific tumor cells. (J) Specifically designed bispecific molecules are also used to specifically eliminate tumor cells because these special molecules bind to activate NK cell receptors on one side and tumor antigens on the other side. (K) NK cells can enhance or attenuate the activity of macrophages and T cells through the production of IFN-γ and IL-10.

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Full record of Chinese tea culture knowledge

Chinese tea has a long history, a variety of tea varieties, colorful, competing for beauty, like a hundred gardens in spring, so that thousands of mountains and rivers are especially enchanting.

Chinese tea culture is extensive and profound, in recent years, the more and more people explore tea culture, the knowledge of tea culture is numerous, then let’s take a look at the Chinese tea culture knowledge carefully recommended by Xiaobian for everyone, I hope to help you.

1. How did the word “tea” develop?

When humans first discovered the use of tea, they would give it a name, such as Shennong found that the leaves on the tea tree had eaten detoxification, and he called this tree “tea”. Before the Tang Dynasty, there were “tea”, “false”, “society”, “tea” and “masuyi”, which were unified into “tea” when Lu Yu wrote “Tea Classic” in the Tang Dynasty.

2. Who is the Tea Lord?

The tea saint is usually Lu Yu of the Tang Dynasty, who lived in a monastery from childhood and was brought up by an old monk. He has extensive and in-depth research on tea tree, tea and tea ceremony, and has written the world’s first tea monograph “Tea Classic”. In the book, Lu Yu introduced the origin, distribution, living conditions, planting, varieties, tea picking and tea making, introduced the relevant vessels in the book, and introduced how to boil tea, how to brew it, how to drink it, what water to use, and related stories. This was the first comprehensive and systematic description of tea. It has important guiding significance for the later tea research and even today’s tea research.

3. What is tea ceremony, tea art and tea culture?

Tea ceremony is about the truth of tea, tea can contain the truth; Tea art is the art of drinking tea, making tea, appreciating tea and interpreting tea; Tea culture takes tea as the carrier to spread, deduce and sublimate the national and local fine traditional culture. Whether tea ceremony, tea art, tea culture should have arisen in the Jin and Sui dynasties before the Tang Dynasty, and the later generations only developed and spread.

4. Who wrote the Great View of Tea?

Zhao Ji, Emperor Huizong of the late Northern Song Dynasty, was a foolish king, but he was a good artist. He was good at playing piano, playing chess, writing and painting. Planting tea, making tea, and drinking tea have been practiced, and then wrote a tea book, namely, “Grand View of Tea”.

Full record of Chinese tea culture knowledge0

5. Who is the Tea God?

Generally refers to Shennong, because Shennong is the representative of the ancient human in the legend, Shennong is the symbol of human discovery and use of tea tree.

6. Who is Cha Zu?

The brother nationalities in Yunnan regard Zhuge Liang as the tea ancestor in The Three Kingdoms, saying that Zhuge Liang distributed tea seeds to the multi-ethnic brothers along the way during the southern expedition, and tea trees, tea fields and tea mountains have flourished since then. Sichuan people regard Wu Lizhen of the Western Han Dynasty as the ancestor of tea, saying that he is the pioneer of tea planting. The tea trees he moved from Xianshan Mountain and planted on the top of Mengding Mountain are still here today, achieving the generation reputation of “water in the Yangtze River, tea on the top of Mengding Mountain”.

7. What does Cha Shou mean?

The tea word is divided into “twenty” and “eighty-eight”, twenty plus eighty-eight equals one hundred and eight, and the tea life is one hundred and eight years old.

Full record of Chinese tea culture knowledge0

8. What does “go for tea” mean?

According to legend, there was a monk named Congren in the Tang Dynasty, who often lived in Zhaozhou Guanyin Temple, known as Zhaozhou Ancient Buddha. Because of tea addiction, always say “eat tea to go” before each speech, and later this sentence “eat tea to go” became Zen Lin French.

9. What is the best tea couplet?

“Can clear the heart”, this is a poem.

In the Northern Song Dynasty, Su Shi wrote a couplet: Sit, please sit, please sit up; Tea, tea, fragrant tea.

There is also a “smoke lock pond willow” poetic and picturesque, the side implies gold, wood, water, fire, earth five elements, 400 years no one can be right, but by a professor of Peking University in their own tea room when the sudden inspiration to a “tea cooking wall spring”.

10. What is a tea table?

Tea table, table and attached tea set, flower arrangement, laying, environmental background, tea artistes wearing, etc.

11 Briefly describe the ancient Tea Horse Road.

The ancient tea Horse Road originated from the “tea horse trade” in the Tang and Song dynasties. People in the border areas of Kang and Tibet rely on beef and mutton as their staple food and need tea to break down fat and prevent dryness and heat. Large numbers of horses were needed for the inland campaign. Thus came the trade of tea and horses. The ancient Tea Horse Road is mainly divided into Yunnan-Tibet line and Sichuan-Tibet Line, in addition to a number of branch lines, extending outwards to West Asia, Central Asia, as far as Europe.

Full record of Chinese tea culture knowledge0

12 Why is the Opium War really a tea war?

In the 18th century, the world’s silver was flowing into China because of the tea trade, and the British trade with China was less than one-tenth of China’s exports, so the British decided to import opium to China. The opium trade brought great profits to Britain, which made China turn from a trade superpower into an import superpower, and a serious silver shortage occurred in China. The government has banned smoking. The smoking ban violated the interests of the United Kingdom, which triggered the Opium War between China and Britain.

13 Briefly describe the Boston Tea Party in the United States.

In 1773, the British government dumped the overstocked tea of the East India Company into the North American colonies, causing anger among the local people. More than 8,000 people gathered in Boston to protest, and more than 60 people dumped 342 chests of tea from an East India Company ship into the sea in what became known as the Boston Tea Party. The British military exerted pressure on the town, causing the people to revolt together, which led to the American Revolutionary War. On July 4, 1776, the United States of America was proclaimed.

14 How fermented is black tea? Health benefits? Water temperature? How to keep it?

Black tea is fully fermented tea; Tea mild, help gastrointestinal digestion, promote appetite, diuresis, eliminate edema, antibacterial, prevent viral cold, prevent tooth decay and food poisoning, reduce blood sugar value; Water temperature 80℃; Shelf life 36 months, room temperature storage.

15 The degree of fermentation of dark tea? Health benefits? Water temperature? How to keep it?

Dark tea is fully fermented tea (raw tea does not ferment); Anti-radiation, anti-cancer, help sober up, promote digestion, weight loss, delay aging, lower cholesterol, lower blood pressure, inhibit arteriosclerosis, and so on, to greasy; The water temperature is 95-100℃, the older the more fragrant, the room temperature storage.

Full record of Chinese tea culture knowledge0

16 The degree of fermentation of white tea? Health benefits? Water temperature? How to keep it?

White tea is slightly fermented tea; Decanting, clearing heat and moistening lung, flattening liver and benefiting blood, anti-inflammatory and detoxifying, reducing blood pressure and fat,

Eliminate fatigue, etc.; Water temperature 80-90 ℃; The shelf life is more fragrant, one year tea, three years medicine, seven years treasure, room temperature storage.

17 The degree of fermentation of yellow tea? Health benefits? Water temperature? How to keep it?

Yellow tea is light fermented tea; Refresh the mind, digestion and stagnation, on indigestion, loss of appetite, lazy movement and obesity have a certain effect; Water temperature 80-90 ℃; Shelf life 3-6 months, refrigerated storage.

18 What are the types of reprocessed tea?

Scented tea: tea + flower, jasmine tea, rose tea, chrysanthemum tea, osmanthus tea, etc.

Fruit tea: tea + fruit, lychee tea, lemon tea, citrus tea, hawthorn tea, etc.

Extraction of tea: Using tea as raw material, extracting soluble matter in tea with hot water, filtering to remove tea residue.

Health tea: tea brewed with herbs or ingredients, such as burdock tea, ganoderma tea, buckwheat tea, etc.

Full record of Chinese tea culture knowledge0

19 Briefly describe the mother tree of Da Hongpao

There are 6 Dahongpao mother trees, which are of shrub type. The leaf quality is thicker, the bud head is red, when the sun shines on the tea tree and the rock, the rock reflects the light, and the tea tree is bright red like fire, if the red robe covers the tree, so the name “Da Hong robe”. Dahongpao, iron arhat, white rooster’s comb and water golden turtle together called Wuyi rock tea four clusters.

20 Brief description of Oriental beauty

Oriental beauty tea originated in Hsinchu, Taiwan, heavily fermented oolong tea, tea heart has a thick crystal fluffiness, was sucked by Ye Chan, the taste is strong and sweet, and with the aroma of ripe fruit and honey, according to the British Queen after tasting, gave the name “Oriental beauty”. Heyuan purple gold also produces Oriental beauty.

kinds of tea, tea drinking is not equal to having a tea culture, is only a prerequisite for the formation of tea culture, but also must have the participation of scholars and cultural connotation. The Classic of Tea, written by Lu Yu in the Tang Dynasty, systematically summarized the experience of tea production and drinking in the Tang Dynasty and before, and put forward the spirit of tea ceremony of fine practice and frugality. A group of intellectuals such as Lu Yu and Jiao Ran attach great importance to the spiritual enjoyment and moral standards of tea, pay attention to tea drinking utensils, tea drinking water and tea cooking art, and blend with the philosophical thoughts of Confucianism, Taoism and Buddhism, and gradually make people enter their spiritual field. In the process of drinking tea, some scholars and literati also created a lot of tea poems. In the Poems of the Whole Tang Dynasty alone, more than 400 poems of more than 100 poets have been handed down so far, thus laying the foundation of the Han tea culture.

Full record of Chinese tea culture knowledge0

Tea is a plant, edible, toxic, long easy health, longevity, tea is the best, can also be used for medicine, so there is a tea is the essence of heaven and earth, shun is the fundamental of life. Therefore, there is tea in Taoism as a tea product.

Han people drink tea, pay attention to a “product” word. When guests arrive, the etiquette of making and serving tea is essential. When there are visitors to visit, you can ask for advice, choose the most suitable guest taste and the best tea set to welcome guests. When offering tea to guests, it is also necessary to mix tea appropriately. When the host accompanies the guests to drink tea, it is necessary to pay attention to the residual amount of tea in the guests’ cups and POTS. Generally, tea is made in teacup. If half of the tea has been drunk, it is necessary to add boiling water and add it with drinking, so that the concentration of tea is basically consistent and the water temperature is suitable. When drinking tea, you can also appropriately add tea, candy, dishes, etc., to adjust the taste and snack effect.

Chinese tea culture is extensive and profound, in recent years, the more and more people explore tea culture, tea culture knowledge is large, I hope to help you.