Natural Killer T (NKT) Cells

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With a commitment to advancing scientific discovery, Creative BioMart offers a comprehensive range of high-quality products, expert services, and valuable resources to support and accelerate NKT cell research.

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About Natural Killer T (NKT) Cells

Natural Killer T (NKT) cells are a unique subset of lymphocytes that bridge the innate and adaptive immune systems. They possess characteristics of both conventional T cells and natural killer (NK) cells, hence the name "Natural Killer T cells." NKT cells express a T cell receptor (TCR) like conventional T cells but also express NK cell receptors, allowing them to recognize a broad range of antigens and respond rapidly to infections, tumors, and autoimmune disorders.

Characteristics and Subsets of NKT Cells

1. Expression of TCR and NK Cell Receptors: NKT cells express a semi-invariant TCR composed of an invariant alpha chain (Vα14-Jα18 in mice, Vα24-Jα18 in humans) paired with a limited repertoire of beta chains. This TCR recognizes lipid antigens presented by the non-polymorphic major histocompatibility complex class I-like molecule called CD1d. In addition, NKT cells express NK cell receptors, such as CD94/NKG2, which interact with MHC class I-like molecules.

2. Subsets of NKT Cells: NKT cells can be classified into two major subsets based on the expression of specific surface markers and cytokine production:

• Type I NKT cells (iNKT cells): They are the most well-characterized subset and express an invariant TCR α-chain (Vα14-Jα18 in mice, Vα24-Jα18 in humans) paired with a limited repertoire of β chains. iNKT cells predominantly produce pro-inflammatory cytokines, such as interferon-gamma (IFN-γ), and play a crucial role in antimicrobial responses, tumor surveillance, and autoimmune diseases.
• Type II NKT cells: They are a heterogeneous population that expresses diverse TCRs. Type II NKT cells have more limited antigen recognition capabilities and exhibit distinct functional properties compared to iNKT cells. Their functions are still being actively investigated.

Fig.1 Overview of the different functional human NKT cell subsets. (Krijgsman D, et al., 2018)

Functions of NKT Cells

• Rapid Cytokine Production: Upon activation by CD1d-presented antigens, NKT cells can rapidly produce a variety of cytokines, including IFN-γ, interleukin-4 (IL-4), IL-17, and tumor necrosis factor-alpha (TNF-α). This cytokine production allows NKT cells to modulate immune responses and influence the activities of other immune cells.
• Immune Regulation: NKT cells play a critical role in immune regulation by interacting with various immune cells. They can stimulate or suppress immune responses depending on the context. For example, iNKT cells can enhance the activation of dendritic cells, B cells, and conventional T cells, thereby influencing adaptive immune responses. They can also regulate the functions of other immune cells, such as regulatory T cells and NK cells.
• Tumor Surveillance: NKT cells are involved in immune surveillance against tumors. They can directly recognize and kill tumor cells through the release of cytotoxic granules or by inducing apoptosis. Additionally, NKT cells can produce cytokines that stimulate anti-tumor immune responses, promote the recruitment of other immune cells, and enhance the activity of cytotoxic T cells.
• Host Defense against Infections: NKT cells contribute to host defense against various microbial infections. They can recognize glycolipid antigens derived from bacteria, viruses, and parasites, leading to rapid cytokine production and activation of other immune cells. This helps in early control of infections and shaping subsequent immune responses.

Molecules Associated with NKT Cells Functions

The functions of NKT cells are regulated by a complex interplay of various molecules. These molecules are involved in NKT cell activation, antigen recognition, co-stimulation, and effector functions. Understanding these molecules is crucial for unraveling the mechanisms underlying NKT cell biology and for developing targeted therapies. Here are some key molecules associated with NKT cell functions: (These molecules are just examples.):

Key molecules type	Key molecules and functions
T Cell Receptor (TCR)	The TCR plays a central role in NKT cell antigen recognition. NKT cells express a semi-invariant TCR composed of an invariant α chain (Vα14-Jα18 in mice, Vα24-Jα18 in humans) paired with a limited repertoire of β chains. This TCR recognizes lipid antigens presented by the non-polymorphic major histocompatibility complex class I-like molecule called CD1d.
CD1d	CD1d is a non-classical MHC class I-like molecule that presents lipid antigens to NKT cells. It is expressed on various antigen-presenting cells, such as dendritic cells, macrophages, and B cells. Interaction between the TCR on NKT cells and the lipid antigens presented by CD1d is essential for NKT cell activation and effector functions.
Co-stimulatory Molecules	Co-stimulatory molecules provide additional signals to enhance NKT cell activation and effector functions. Some important co-stimulatory molecules include: CD28: Interaction between CD28 on NKT cells and CD80/CD86 on antigen-presenting cells provides a co-stimulatory signal for NKT cell activation. CD40: Engagement of CD40 on antigen-presenting cells by CD40 ligand (CD40L) expressed on NKT cells promotes antigen presentation and cytokine production. ICOS: Inducible co-stimulator (ICOS) on NKT cells interacts with its ligand ICOSL on antigen-presenting cells, contributing to NKT cell activation and cytokine production.
Cytokines	Cytokines play a critical role in NKT cell functions by modulating their activation, expansion, and effector responses. Some important cytokines involved in NKT cell biology include: Interleukin-2 (IL-2): IL-2 is crucial for NKT cell expansion and survival. IL-12 and IL-18: These cytokines promote NKT cell activation and production of interferon-gamma (IFN-γ), a key effector cytokine. IL-4: IL-4 is involved in the activation of Type II NKT cells and the production of Th2-associated cytokines.
NK Cell Receptors	NKT cells also express natural killer (NK) cell receptors, which play a role in their activation and effector functions. Some important NK cell receptors expressed by NKT cells include: CD94/NKG2: CD94/NKG2 receptors interact with MHC class I-like molecules, including CD1d, and contribute to NKT cell activation and cytotoxicity. Natural cytotoxicity receptors (NCRs): NCRs, such as NKp30, NKp44, and NKp46, are involved in NKT cell-mediated cytotoxicity against target cells.
Cytotoxic Granules	NKT cells have cytotoxic capabilities and can release cytotoxic granules containing perforin and granzymes upon activation. Perforin creates pores in the target cell membrane, allowing granzymes to enter and induce target cell apoptosis.
Transcription Factors	Transcription factors play a crucial role in regulating NKT cell development, differentiation, and effector functions. Some important transcription factors involved in NKT cell biology include: T-bet: T-bet is a transcription factor associated with Type I NKT cell differentiation and the production of IFN-γ. GATA-3: GATA-3 is involved in the development and function of Type II NKT cells and the production of Th2-associated cytokines.

Understanding the molecular players involved in NKT cell functions provides insights into their activation, regulation, and effector responses. Targeting these molecules holds promise for developing therapeutic strategies aimed at modulating NKT cell responses in various diseases, including cancer, autoimmune disorders, and infectious diseases. Further research is needed to uncover additional molecules and their intricate interactions in the context of NKT cell biology.

Role of NKT Cell-Associated Molecules in Diseases

NKT cell-associated molecules play crucial roles in the development and progression of various diseases. These molecules are involved in modulating NKT cell activation, effector functions, and interactions with other immune cells, thereby influencing the immune responses associated with different diseases. Here are some examples of the role of NKT cell-associated molecules in specific diseases:

1. Autoimmune Diseases

NKT cells and their associated molecules have been implicated in the pathogenesis of autoimmune diseases, where the immune system mistakenly attacks self-tissues. Dysregulation or dysfunction of NKT cell-associated molecules can contribute to the development of autoimmune diseases such as:

• CD1d: Alterations in CD1d expression or function can affect NKT cell activation and tolerance, potentially leading to autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS).
• Cytokines: Imbalances in cytokine production by NKT cells, such as elevated levels of interleukin-4 (IL-4) or interferon-gamma (IFN-γ), can promote autoimmune responses and contribute to diseases like type 1 diabetes and inflammatory bowel disease.

2. Infectious Diseases

NKT cells play a critical role in host defense against microbial infections by rapidly responding to pathogens and modulating immune responses. NKT cell-associated molecules have an impact on the immune response to infectious diseases, including:

• CD1d: Expression of CD1d and presentation of microbial antigens by CD1d molecules are essential for NKT cell recognition and response to infectious agents. Dysregulation of CD1d expression can affect NKT cell-mediated immune responses to pathogens.
• Cytokines: NKT cells produce various cytokines, such as IFN-γ and IL-4, which can regulate immune responses during infections. Dysregulated cytokine production by NKT cells can impact disease outcomes and host defense against pathogens.

3. Cancer

NKT cells have both anti-tumor and tumor-promoting activities, and their function is regulated by interactions with tumor cells and the tumor microenvironment. NKT cell-associated molecules play a role in tumor immunity and tumor progression, including:

• CD1d: Expression of CD1d on tumor cells allows NKT cells to recognize and respond to tumor antigens. Alterations in CD1d expression or function can affect NKT cell activation and anti-tumor immune responses.
• Co-stimulatory Molecules: Interactions between co-stimulatory molecules, such as CD80/CD86 on antigen-presenting cells and their receptors on NKT cells, can influence NKT cell activation and effector functions in the tumor microenvironment.

4. Allergic and Asthmatic Disorders

NKT cells are involved in regulating immune responses associated with allergic diseases and asthma. NKT cell-associated molecules have an impact on the development and progression of these diseases, including:

• CD1d: Interactions between CD1d molecules and NKT cell receptors are crucial for NKT cell activation and subsequent immune responses in allergic and asthmatic disorders.
• Cytokines: NKT cells produce cytokines, such as IL-4 and IL-13, which play a role in promoting allergic inflammation. Dysregulated cytokine production by NKT cells can contribute to the development and severity of allergic diseases.

Understanding the role of NKT cell-associated molecules in disease is important for developing targeted therapies that modulate NKT cell responses and restore immune homeostasis in various pathological conditions. However, it's important to note that the specific roles of these molecules can vary depending on the disease context and individual patient characteristics. Further research is needed to fully elucidate the mechanisms by which NKT cell-associated molecules contribute to disease pathogenesis and identify potential therapeutic targets.

Fig.2 The dual role of NKT cells in cancer. (Krijgsman D, et al., 2018)

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Related References

1. Krijgsman D, Hokland M, Kuppen PJK. The role of natural killer T cells in cancer-a phenotypical and functional approach. Front Immunol. 2018;9:367.
2. Taniguchi M, Harada M, Dashtsoodol N, Kojo S. Discovery of NKT cells and development of NKT cell-targeted anti-tumor immunotherapy. Proc Jpn Acad Ser B Phys Biol Sci. 2015;91(7):292-304.
3. Wu L, Van Kaer L. Natural killer T cells in health and disease. Front Biosci (Schol Ed). 2011;3(1):236-251.
4. Vivier E, Ugolini S, Blaise D, Chabannon C, Brossay L. Targeting natural killer cells and natural killer T cells in cancer. Nat Rev Immunol. 2012;12(4):239-252.
5. Brailey PM, Lebrusant-Fernandez M, Barral P. NKT cells and the regulation of intestinal immunity: a two-way street. FEBS J. 2020;287(9):1686-1699.
6. Nair S, Dhodapkar MV. Natural killer T cells in cancer immunotherapy. Front Immunol. 2017;8:1178.