Natural killer T cell

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Natural killer T (NKT) cells are a heterogeneous group of T cells that share properties of both T cells and natural killer cells. Many of these cells recognize the non-polymorphic CD1d molecule, an antigen-presenting molecule that binds self and foreign lipids and glycolipids. They constitute only approximately 1% of all peripheral blood T cells. [1] Natural killer T cells should neither be confused with natural killer cells nor killer T cells (cytotoxic T cells).

Contents

Nomenclature

The term "NK T cells" was first used in mice to define a subset of T cells that expressed the natural killer (NK) cell-associated marker NK1.1 (CD161). It is now generally accepted that the term "NKT cells" refers to CD1d-restricted T cells, present in mice and humans, some of which coexpress a heavily biased, semi-invariant T-cell receptor and NK cell markers. [2]

Molecular characterization

NKT cells are a subset of T cells that coexpress an αβ T-cell receptor, but also express a variety of molecular markers that are typically associated with NK cells, such as NK1.1. The best-known NKT cells differ from conventional αβ T cells in that their T-cell receptors are far more limited in diversity ('invariant' or 'type 1' NKT). [3] They and other CD1d-restricted T cells ('type 2' NKT) recognize lipids and glycolipids presented by CD1d molecules, a member of the CD1 family of antigen-presenting molecules, rather than peptide-major histocompatibility complexes (MHCs). As such, NKT cells are important in recognizing glycolipids from organisms such as Mycobacterium , which causes tuberculosis.

NKT cells include both NK1.1+ and NK1.1−, as well as CD4+, CD4−, CD8+ and CD8− cells. Natural killer T cells can share other features with NK cells, as well, such as CD16 and CD56 expression and granzyme production. [4] [5]

Invariant natural killer T (iNKT) cells express high levels of and are dependent on the transcriptional regulator promyelocytic leukemia zinc finger for their development. [6] [7]

Classification

Classification of natural killer T cells into three groups has been proposed: [2]

Type 1 NKTType 2 NKTNKT-like
Other namesclassical NKT
invariant NKT (iNKT)
Vα14i NKT (mouse)
Vα24i NKT (human)		non-classical NKT
diverse NKT		NK1.1+ T cells
CD3+ CD56+ T cells
Restriction CD1dCD1dMHC, other?
α-GalCer
reactivity		+--
T-cell-receptor repertoireVα14-Jα18:
Vβ8.2, 7, 2 (mouse)
Vα24-Jα18:
Vβ11 (human)		diversediverse

Invariant NKT (iNKT) cells

The best-known subset of CD1d-dependent NKT cells expresses an invariant T-cell receptor (TCR) α chain. These are referred to as type I or invariant NKT cells (iNKT) cells. They are notable for their ability to respond rapidly to danger signals and pro-inflammatory cytokines. Once activated, they engage in effector functions, like NK transactivation, T cell activation and differentiation, B cell activation, dendritic cell activation and cross-presentation activity, and macrophage activation.

iNKT cells recognize lipid antigens presented by CD1d, a non-polymorphic major histocompatibility complex class I-like antigen presenting molecule. These cells are conserved between humans and mice. The highly conserved TCR is made of Va24-Ja18 paired with Vb11 in humans, which is specific for glycolipid antigens. [8] The best known antigen of iNKT cells is alpha-galactosylceramide (αGalCer), which is a synthetic form of a chemical purified from the deep sea sponge Agelas mauritianus. [9] iNKT cells develop in the thymus, and distribute to the periphery. They are most commonly found in the liver, but are also found in the thymus, spleen, peripheral blood, bone marrow and fat tissue. In comparison to mice, humans have fewer iNKT cells and have a wide variation in the amount of circulating iNKT cells. [8]

Currently, there are five major distinct iNKT cell subsets. These subset cells produce a different set of cytokines once activated. The subtypes iNKT1, iNKT2 and iNKT17 mirror Th Cell subsets in cytokine production. In addition there are subtypes specialized in T follicular helper-like function and IL-10 dependent regulatory functions. [10] Once activated iNKT cells can impact the type and strength of an immune response. They engage in cross talk with other immune cells, like dendritic cells, neutrophils and lymphocytes. [11] Activation occurs by engagement with their invariant TCR. iNKT cells can also be indirectly activated through cytokine signaling. [8]

While iNKT cells are not very numerous, their unique properties makes them an important regulatory cell that can influence how the immune system develops. [12] They are known to play a role in chronic inflammatory diseases like autoimmune disease, asthma and metabolic syndrome. In human autoimmune diseases, their numbers are decreased in peripheral blood. It is not clear whether this is a cause or effect of the disease. Absence of microbe exposure in early development led to increased iNKT cells and immune morbidity in a mouse model. [13]

Function

Upon activation, NKT cells are able to produce large quantities of interferon gamma, IL-4, and granulocyte-macrophage colony-stimulating factor, as well as multiple other cytokines and chemokines (such as IL-2, IL-13, IL-17, IL-21, and TNF-alpha).

NKT cells recognize protected microbial lipid agents which are presented by CD1d-expressing antigen presenting cells. This serves as a pathway for NKT cells to fight against infections and enhance the humoral immunity. The NKT cells provide support and help to B cells which act as a microbial defense and aid in targeting for B-cell vaccines. [14]

Significance

NKT cells seem to be essential for several aspects of immunity because their dysfunction or deficiency has been shown to lead to the development of autoimmune diseases such as diabetes, autoinflammatory diseases such as atherosclerosis, and cancers. NKT cells have recently been implicated in the disease progression of human asthma. [15]

The clinical potential of NKT cells lies in the rapid release of cytokines (such as IL-2, IFN-gamma, TNF-alpha, and IL-4) that promote or suppress different immune responses.

Most clinical trials with NKT cells have been performed with cytokine-induced killer cells (CIK). [16]

See also

Related Research Articles

<span class="mw-page-title-main">T cell</span> White blood cells of the immune system

T cells are one of the important types of white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.

<span class="mw-page-title-main">B cell</span> Type of white blood cell

B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasma membrane where they serve as a part of B-cell receptors. When a naïve or memory B cell is activated by an antigen, it proliferates and differentiates into an antibody-secreting effector cell, known as a plasmablast or plasma cell. Additionally, B cells present antigens and secrete cytokines. In mammals, B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick, which is why the 'B' stands for bursa and not bone marrow as commonly believed.

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways.

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

<span class="mw-page-title-main">Natural killer cell</span> Type of cytotoxic lymphocyte

Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cell and other intracellular pathogens acting at around 3 days after infection, and respond to tumor formation. Typically, immune cells detect the major histocompatibility complex (MHC) presented on infected cell surfaces, triggering cytokine release, causing the death of the infected cell by lysis or apoptosis. NK cells are unique, however, as they have the ability to recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class 1. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

<span class="mw-page-title-main">Cell-mediated immunity</span> Immune response that does not involve antibodies

Cell-mediated immunity or cellular immunity is an immune response that does not involve antibodies. Rather, cell-mediated immunity is the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen.

CD1 is a family of glycoproteins expressed on the surface of various human antigen-presenting cells. CD1 glycoproteins are structurally related to the class I MHC molecules, however, in contrast to MHC class 1 proteins, they present lipids, glycolipids and small molecules antigens to T cells. Both αβ and γδ T cells recognise CD1 molecules.

<span class="mw-page-title-main">Fc receptor</span> Surface protein important to the immune system

In immunology, a Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells – that contribute to the protective functions of the immune system. Its name is derived from its binding specificity for a part of an antibody known as the Fc region. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection.

Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear.

<span class="mw-page-title-main">Immunological synapse</span> Interface between lymphocyte and target cell

In immunology, an immunological synapse is the interface between an antigen-presenting cell or target cell and a lymphocyte such as a T/B cell or Natural Killer cell. The interface was originally named after the neuronal synapse, with which it shares the main structural pattern. An immunological synapse consists of molecules involved in T cell activation, which compose typical patterns—activation clusters. Immunological synapses are the subject of much ongoing research.

<span class="mw-page-title-main">CD1D</span> Mammalian protein found in Homo sapiens

CD1D is the human gene that encodes the protein CD1d, a member of the CD1 family of glycoproteins expressed on the surface of various human antigen-presenting cells. They are non-classical MHC proteins, related to the class I MHC proteins, and are involved in the presentation of lipid antigens to T cells. CD1d is the only member of the group 2 CD1 molecules.

Gamma delta T cells are T cells that have a γδ T-cell receptor (TCR) on their surface. Most T cells are αβ T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, γδ T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells, but are at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

T helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen. Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). Th3 have been described both in mice and human as CD4+FOXP3− regulatory T cells. Th3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+CD25−FOXP3−LAP+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.

Mucosal-associated invariant T cells make up a subset of T cells in the immune system that display innate, effector-like qualities. In humans, MAIT cells are found in the blood, liver, lungs, and mucosa, defending against microbial activity and infection. The MHC class I-like protein, MR1, is responsible for presenting bacterially-produced vitamin B2 and B9 metabolites to MAIT cells. After the presentation of foreign antigen by MR1, MAIT cells secrete pro-inflammatory cytokines and are capable of lysing bacterially-infected cells. MAIT cells can also be activated through MR1-independent signaling. In addition to possessing innate-like functions, this T cell subset supports the adaptive immune response and has a memory-like phenotype. Furthermore, MAIT cells are thought to play a role in autoimmune diseases, such as multiple sclerosis, arthritis and inflammatory bowel disease, although definitive evidence is yet to be published.

Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology, absence of rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.

Cytokine-induced killer cells (CIK) cells are a group of immune effector cells featuring a mixed T- and natural killer (NK) cell-like phenotype. They are generated by ex vivo incubation of human peripheral blood mononuclear cells (PBMC) or cord blood mononuclear cells with interferon-gamma (IFN-γ), anti-CD3 antibody, recombinant human interleukin (IL)-1 and recombinant human interleukin (IL)-2.

<span class="mw-page-title-main">Adaptive NK cell</span> Specialized subtype of cytotoxic lymphocyte

An adaptive natural killer (NK) cell or memory-like NK cell is a specialized natural killer cell that has the potential to form immunological memory. They can be distinguished from cytotoxic NK (cNK) cells by their receptor expression profile and epigenome. Adaptive NK cells are so named for properties which they share with the adaptive immune system. Though adaptive NK cells do not possess antigen specificity, they exhibit dynamic expansions of defined cell subsets, increased proliferation and long-term persistence for up to 3 months in vivo, high IFN-γ production, potent cytotoxic activity upon ex vivo restimulation, and protective memory responses.

alpha-Galactosylceramide is a synthetic glycolipid derived from structure-activity relationship studies of galactosylceramides isolated from the marine sponge Agelas mauritianus. α-GalCer is a strong immunostimulant and shows potent anti-tumour activity in many in vivo models.

Cd1-restricted T cells are part of the unconventional T cell family, they are stimulated by exposure to CD1+ antigen presenting cells (APCs). Many CD1-restricted T cells are rapidly stimulated to carry out helper and effector functions upon interaction with CD1-expressing antigen-presenting cells. CD1-restricted T cells regulate host defence, antitumor immunity and the balance between tolerance and autoimmunity.

Mitchell Kronenberg is an American immunologist and the chief scientific officer at La Jolla Institute for Immunology. He served as president of the institute from 2003 to 2021. 

References

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  3. ↑ de Araújo, ND; Gama, FM; de Souza Barros, M; Ribeiro, TLP; Alves, FS; Xabregas, LA; Tarragô, AM; Malheiro, A; Costa, AG (2021). "Translating Unconventional T Cells and Their Roles in Leukemia Antitumor Immunity". Journal of Immunology Research. 2021: 6633824. doi: 10.1155/2021/6633824 . PMC   7808823 . PMID   33506055.
  4. ↑ Van der Vliet, HJ; Nishi N; Koezuka Y; Peyrat MA; Von Blomberg BM; Van den Eertwegh AJ; Pinedo HM; Giaccone G; Scheper RJ (1999). "Effects of alphagalactosylceramide (KRN7000), interleukin-12 and interleukin-7 on phenotype and cytokine profile of human Va24+ Vb11+ T cells". Immunology. 98 (4): 557–563. doi:10.1046/j.1365-2567.1999.00920.x. PMC   2326955 . PMID   10594688.
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  6. ↑ Kovalovsky D, Uche OU, et al. (Sep 2008). "The BTB-zinc finger transcriptional regulator PLZF controls the development of invariant natural killer T cell effector functions". Nature Immunology. 9 (9): 1055–64. doi:10.1038/ni.1641. PMC   2662733 . PMID   18660811.
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  8. 1 2 3 Brennan, Patrick J.; Brigl, Manfred; Brenner, Michael B. (2013-02-01). "Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions". Nature Reviews Immunology. 13 (2): 101–117. doi:10.1038/nri3369. ISSN   1474-1733. PMID   23334244. S2CID   205491870.
  9. ↑ Kawano, T.; Cui, J.; Koezuka, Y.; Toura, I.; Kaneko, Y.; Motoki, K.; Ueno, H.; Nakagawa, R.; Sato, H. (1997-11-28). "CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides". Science. 278 (5343): 1626–1629. Bibcode:1997Sci...278.1626K. doi:10.1126/science.278.5343.1626. ISSN   0036-8075. PMID   9374463.
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