April 17, 2024

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What are NK (Natural killer) cell biological characteristics?

What are NK (Natural killer) cell biological characteristics?


What are NK (Natural killer) cell biological characteristics?


NK cells are important players in the innate immune system, constituting the first line of defense against cancer cells. Natural killer (NK) cells were defined by Herberman in 1976, 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, the distribution of NK cells in healthy tissues is different, in bone marrow, spleen, liver, lung, skin , Kidney, uterus and secondary lymphoid tissues have higher concentrations.

NK cells are derived from CD34+ common lymphoid progenitors and differentiate into immature and mature NK cells in the bone marrow (BM). It then distributes to lymphoid and nonlymphatic peripheral organs and tissues, including PB, spleen, lung, liver and uterus.


NK cell development

NK cells have a cytotoxic capacity similar to CD8+ T cells that play a role in adaptive immunity but lack CD3 and T cell receptor (TCR). NK cells mainly circulate in the blood, accounting for about 5-10% of peripheral blood mononuclear cells (PBMC), and exist 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 turnover 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 the major histocompatibility complex-I (MHC-I), Helps NK cells gain permission and avoid attacking healthy normal cells. Interestingly, tumor cells always lack or only express low levels of MHC-I to escape CD8+ T cell-mediated cytotoxicity, while licensed NK cells are fully activated.

However, tumor cells also express molecules that activate NK cells, such as MHC class I peptide-associated sequence A (MICA) and MICB, supporting the use of NK cells as anticancer agents.

In addition, non-permissive NK cells also play important roles in vivo, such as eliminating murine cytomegalovirus (MCMV) infection and MHC-I+ cells.


To date, the survival and development of NK cells is considered to be mainly dependent on cytokines (especially IL-2 and IL-15) and transcription factors (Nfil3, Id2 and Tox for development, 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 associated signals is a potential option to promote NK cell-induced cancer cytotoxicity.

As previously reported, ablation of cytokine-inducible SH2-containing protein (CIS) negatively regulates IL-15 to limit NK cell function, prevents metastasis and enhances CTLA-4 and PD-1 blockade therapy in vivo.



Surface Molecules of NK Cells

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 with one or two simple molecules or conventional 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 subsets.

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 a recent study, based on the consensus of adding more functional proteins rather than surface molecules to the classification, it was proposed that natural cytotoxicity receptor 46 (NKp46), which belongs to natural cytotoxicity receptors (NCRs), should also be included in this Conceptual NK cell system in panel.



Activation 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 discriminate against incalculable antigens in vivo, they rely on ‘missing self’ and ‘induced self’ modes to recognize target cells by maintaining a precise balance between activating co-stimulation and repression.

Signaling (mainly via functional receptors). These interacting signals ultimately determine the activation and functional status of NK cells.


Activation signals include cytokine-binding receptors, integrins, killer receptors (CD16, NKp40, NKp30, and NKp44), receptors that recognize non-self antigens (Ly49H), and other receptors (eg, NKp80, SLAM, CD18, CD2, and TLR3/9).

In general, the activating receptors of NK cells can be divided into at least three types according to their respective ligands, including MHC-I-specific receptors, MHC-I-associated receptors, and MHC-I-independent receptors (Table 1 ).


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

What are NK (Natural killer) cell biological characteristics? What are NK (Natural killer) cell biological characteristics?

Figure 2 NK cell surface receptors and ligands on tumor cells are involved in tumor recognition. NK cells express a set of stimulating (or activating) receptors and inhibitory receptors, and recognize healthy cells and abnormal cells, such as virus-infected or potential tumorigenic cells, through the appearance of MHC-1 receptors.


What are NK (Natural killer) cell biological characteristics?

Figure 3. Regulation of natural killer (NK) cell responses according to the ” missing self ” and ” altered self ” models.

(A) The presence of major histocompatibility complex (MHC)-I , which acts as a ligand for the inhibitory NK cell receptor , and the absence of stress-induced ligands on the surface of healthy cells, results in a major inhibitory signal for NK cells .

(B ) activation of NK cell receptors by the presence of stress-inducible ligands and the downregulation of MHC-I by tumor cells results in a major activation signal for NK cells. [ Color map available at wileyonlinelibrary.com ]

What are NK (Natural killer) cell biological characteristics?



Inhibitory signals mainly include receptors that recognize MHC-I, such as Ly49s, NKG2A, and LLT1, and some receptors that are not related to MHC-I (Table 1). In addition, MHC-I-specific inhibitory receptors can generally be divided into three types according to structure and function: killer cell immunoglobulin-like receptors (KIRs), killer lectin-like receptors (KLRs) and leukocyte immunoglobulin like receptors (LILRs).


NK cell subsets according to maturation 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 lung, NK cells are fully differentiated, whereas in lymph nodes and intestine, NK cells are immature and prodromal.

Single-cell transcriptome analysis of bone marrow and blood NK cells helps illustrate their characteristic changes during development. For example, high expression of TIM-3, CX3CR1 and ZEB2 represents a more mature state.


In conclusion, NK cells in various tissues have different characteristics, have different functions and form close relationships with other stromal cells (Fig. 1).

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 overall NK family. Notably, CD69+ cells are the main type of CD56brightCD16-NK cells.

However, in the thymus, the majority of NK cells are CD56highCD16-CD127+ and highly dependent on GATA3 compared to the CD56+CD16+ subset. In addition, they produced 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, which depends on the surface molecule CXCR6.

In the uterus, most NK cells are CD56brightCD16-, expressing high levels of KIRs. For skin NK cells, it is interesting to detect only a small amount of CD56+CD16+, which is common in peripheral blood.

Interestingly, trNK cells are distinct between subcutaneous (CD56dim) and visceral (CD56bright) adipose tissue and can generally be divided into three groups based on CD49b and Eomes, showing distinct CD49a (CD49b+ Eomes- subgroup) and CD69 expression levels (CD49b-Eomes+ subgroup).



NK Cell Subgroups According to Functional Molecules

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


CD16 is a key receptor for mediating antibody-dependent cellular cytotoxicity (ADCC) and induces phosphorylation of the immunoreceptor tyrosine-activating motif (ITAM). According to time-resolved single-cell assays, NK cell cytotoxicity was suppressed through necrosis and apoptosis.

Thus, FasL/FasR interaction, forin/granzyme release, and Ca2+ influx are all important for NK cell function. However, CD56bright NK cells, similar to helper cells, 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 mainly secrete IFN-γ and IL-5, respectively.


In addition to 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 function. A novel CD8αα+ MHC-II+ phenotype with professional APC capacity is thought to represent unusual AP-NK cells that recognize and eliminate autoreactive T cells and eventually kill them like cNK cells.

Human plasmacytoid dendritic cells (DCs) activated by prophylactic vaccine FSME upregulated the expression of CD56 on their surface.


Invariant natural killer T cells (iNKT) constitute a subset of T cells expressing NK cell markers. NKT is activated by CD1d presenting antigens, not only can secrete Th1 type cytokines, but also secrete Th2 type cytokines to participate in immunity.

Th1-polarized iNKT cells exhibit a tumor-exhausting phenotype, whereas Th2-polarized iNKT cells, similar to polarized T cells, contribute to tumor progression.

Recent studies have also highlighted new functional subtypes of iNKT cells. However, in recent years, iNKT cells have the potential to be defined as a special subset of ILCs due to their close relationship with innate immunity.


NK cells play diverse roles in cancer biology as seen in their development and function. NK cells play an anti-tumor immune role by interacting with cancer cells, stromal cells, extracellular matrix, and especially metabolites .



What are NK (Natural killer) cell biological characteristics?

Figure 4. Different ways of NK cell-mediated tumor killing and immune system regulation:

(A) NK cells are able to enhance T cells by killing immature DCs while promoting IFN-γ- and TNF-α-mediated DC maturation Antigen presentation.

(B) NK cells can specifically recognize cells lacking expression of MHC class I molecules (Missing-self).

(C) ADCC can kill target cells.

(D) Fas/FasL pathway is a very efficient NK cell-mediated cell killing (E) Cytokine pathway can exert anti-tumor potential because cytokines (such as NK cells) secrete various cytokines, such as TNF- alpha.

(F) The NK cell receptor NKG2D recognizes “self-inducing” ligands that are expressed at very high rates in response to activation of tumor-associated 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 self-MHC.

(I) CAR-NK cells designed specifically against overexpressed tumor antigens can also be used to eliminate specific tumor cells.

(J) Specially designed bispecific molecules have also been used to specifically eliminate tumor cells because these specialized molecules bind to activate NK cell receptors on one side and tumor antigens on the other.

(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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What are NK (Natural killer) cell biological characteristics?

What are NK (Natural killer) cell biological characteristics?

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