Cd1-restricted T Cell
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Cd1-restricted T cells are part of the unconventional
T cell T cells (also known as T lymphocytes) are an important part 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 ...
family, they are stimulated by exposure to CD1+
antigen presenting cells An antigen-presenting cell (APC) or accessory cell is a cell that displays an antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes u ...
(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. In general, CD1-restricted T cells are divided according to their CD1 molecule. Humans express four CD1 isoforms divided in 2 groups: * group 1 CD1 (
CD1a CD1a (Cluster of Differentiation 1a) is a human protein encoded by the gene. This gene encodes a member of the CD1 family of transmembrane glycoproteins, which are structurally related to the major histocompatibility complex The major histo ...
,
CD1b T-cell surface glycoprotein CD1b is a protein that in humans is encoded by the CD1B gene. CD1b belongs to group 1 of CD1 family of transmembrane glycoproteins. CD1 molecules are expressed on the surface of numerous different human antigen prese ...
, and CD1c) * group 2 CD1 (
CD1d CD1D is the human gene that encodes the protein CD1d, a member of the CD1 (cluster of differentiation 1) family of glycoproteins expressed on the surface of various human antigen-presenting cells. They are non-classical Major histocompatibility c ...
).


Group 1 CD1-restricted T cells

Group 1 CD1-restricted T cells express diverse αβ T-cell receptors ( TCRs). They can undergo clonal expansion in the periphery after recognition of stimulatory self-lipids or exogenous lipid antigens derived from bacteria. CD1–restricted T cells produce TH1,
IFN-γ Interferon gamma (IFNG or IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. ...
and
TNF-α Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
cytokines and are cytolytic. They can induce TNF-α dependent dentritic cells maturation. Many group 1 CD1–restricted T cells are autoreactive, and autoreactivity is enhanced by stimulation through pattern recognition receptors ( PRRs). CD1a-restricted T cells are among the most frequent self-reactive CD1-restricted T cells in peripheral blood. Moreover, they are common in the skin. Skin CD1a-restricted T cells become activated when in contact with CD1a expressed by Langerhans cells. Upon activation, they produce IFN-𝛾, IL-2, and IL-22, a cytokine with suspected roles in
skin immunity Skin immunity is a property of skin that allows it to resist infections from pathogens. In addition to providing a passive physical barrier against infection, the skin also contains elements of the innate and adaptive immune systems which allows it ...
. CD1a-restricted T cells are unique in the way that their TCR can directly recognize the CD1a molecule without corecognition of a lipid antigen. Self-reactive CD1b-restricted T cells can acquire the phenotype of
T helper 17 T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to actually inhibit Treg differentiation. Howe ...
(TH17) cells and recruit
neutrophil Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...
s. CD1b is expressed at high levels on myeloid dendritic cells in blood and in tissues, and on certain macrophages and other immune cells in the periphery. TCD1b presents many
mycobacterial ''Mycobacterium'' is a genus of over 190 species in the phylum Actinomycetota, assigned its own family, Mycobacteriaceae. This genus includes pathogens known to cause serious diseases in mammals, including tuberculosis ('' M. tuberculosis'') an ...
lipid antigens, including glucose monomycolate (GMM) and free
mycolic acid Mycolic acids are long fatty acids found in the cell walls of Mycobacteriales taxon, a group of bacteria that includes ''Mycobacterium tuberculosis'', the causative agent of the disease tuberculosis. They form the major component of the cell wall ...
(MA) to human T cell clones. The responding T cell clones show effector functions that are consistent with a role in host protection, including Th1 skewed responses, cytotoxicity toward infected cells, and lack of response to uninfected cells or self-lipids. Germline-Encoded Mycolyl lipid reactive (GEM) T cells are defined by the expression of nearly invariant TRAV1-2/TRAJ9+ TCR α chains and CD4+. LDN5-like T cells, named after the clone LDN5, use TRAV17 or TRBV4-1, but have highly variable joining regions and do not seem to preferentially use any particular J segments. LDN5-like cells show conservation in the TCR β chain outside the CDR3. CD1c autoreactive cells has been identified to play a role in tumor detection. CD1–restricted T cells can kill immature dentritic cells that are infected.


CD1d restricted natural killer T cells or group 2 CD1-restricted T cells

Natural killer T (NKT) cells represent unusual cells of the innate immune system because they express a surface receptor that is generated by somatic DNA rearrangement, a hallmark of cells of the adaptive immune system. A hallmark of NKT cells is their capacity to rapidly produce copious amounts of cytokines upon antigenic stimulation, including interferon (IFN)-γ, interleukin (IL)-4, tumor necrosis factor (TNF)- α, and IL-2, which endows these cells with potent immunomodulatory activities. As a result, NKT cells are involved in the regulation of various immune responses, including infectious diseases, tumors, transplants, allergic reactions, autoimmune diseases, and inflammatory diseases. These properties of NKT cells have been utilized in vaccine development and immunotherapy using animal models of infection, tumor metastasis, and autoimmunity. CD1d-restricted NKT cells contribute to host defence by influencing the function of
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s, dentritic cells,
B cell B cells, also known as B lymphocytes, are a type 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 plasm ...
s and
Natural Killer Nature is an inherent character or constitution, particularly of the ecosphere or the universe as a whole. In this general sense nature refers to the laws, elements and phenomena of the physical world, including life. Although humans are par ...
cells. They also contribute to tumor immunosurveillance and can mediate tumor rejection via
interleukin 12 Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, helper T cells and human B-lymphoblast, lymphoblastoid cells (NC-37) in response to antigenic stimulation. IL-12 belongs to the ...
(IL-12) production, Natural Killer or T cell activation, or direct cytolysis. CD1d-restricted NKT cells are divided into 2 groups.


Type I NKT cells

Type I NKT cells are also called ‘invariant NKT cells’ or ‘iNKT cells’, they express an invariant TCRα chain and a limited, but not invariant, range of TCRβ chains. Type I NKT cells are less frequent in humans than in mice (1–3% of T cells in most mouse tissues, 50% in mouse liver and bone marrow, and approximately 0.1% of T cells in human blood). All type I NKT cells recognize the marine sponge-derived glycolipid, α-galactosylceramide (α-GalCer). After the encounter with the antigen Type I NKT cells rapidly become effector cells (minutes to hours) and produce many cytokines. These T cells also have a cytotoxic activity against CD1d+ tumor targets. Furthermore, type I NKT cells upregulate the costimulatory receptor CD154 (CD40 ligand), which, in conjunction with their cytokine production, potently activates DCs to increase expression of the costimulatory molecules
CD80 The Cluster of differentiation 80 (also CD80 and B7-1) is a B7, type I membrane protein in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is c ...
and
CD86 Cluster of Differentiation 86 (also known as CD86 and B7-2) is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells (including memory B-cells), and on other antigen-presenting cells. Along with CD80, CD ...
and produce interleukin 12. This leads to a more efficient presentation of antigen to MHC-restricted adaptive T cells, activation of NK cells and enhanced B cell responses. Thus, NKT cells can promote downstream innate and adaptive immune responses and, in turn, enhance protection against infection and cancer.  Human iNKT cells can be subdivided into subpopulations according to the produced cytokines and the expression of certain transcription factors. iNKT1 cells producing large amounts of IFNγ and a little IL-4, iNKT2 cells producing large amounts of IL-4, and iNKT17 cells secreting IL-17. A special iNKT cell population called iNKT10 has been identified in adipose tissue, which relies on the expression of the transcription factor E4BP4 for its role in maintaining adipose tissue homeostasis.


Type II NKT cells

Type II NKT are also called ‘diverse NKT cells’, they use αβ TCRs that do not conform to the TCR motifs described above. Their TCR sequence is more variable than iNKT cell. cells Type II NKT cells recognize CD1d but lack the highly conserved TCRα chain and reactivity to α-GalCer that classify type I NKT cells. Some type II NKT cells recognize the mammalian glycolipid sulfatide (produced at high concentrations in neuroendocrine tissue) phospholipid antigen lysophosphatidylcholine and some other phospholipid, and lysophospholipid antigens, including phosphatidylglycerol, and
phosphatidylinositol Phosphatidylinositol or inositol phospholipid is a biomolecule. It was initially called "inosite" when it was discovered by Léon Maquenne and Johann Joseph von Scherer in the late 19th century. It was discovered in bacteria but later also found ...
of microbial and mammalian origin. They can also sense gene products of
hepatitis B virus Hepatitis B virus (HBV) is a partially double-stranded DNA virus, a species of the genus '' Orthohepadnavirus'' and a member of the '' Hepadnaviridae'' family of viruses. This virus causes the disease hepatitis B. Classification Hepatitis B ...
by detecting lysophosphatidylethanolamine generated through the cleavage of
phosphatidylethanolamine Phosphatidylethanolamine (PE) is a class of phospholipids found in biological membranes. They are synthesized by the addition of cytidine diphosphate-ethanolamine to diglycerides, releasing cytidine monophosphate. S-Adenosyl methionine, ''S''-Ade ...
by virus-induced phospholipases. Even non-lipidic small molecules, such as PPBF (phenyl 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonate), are antigenic for some type II NKT cells. Thus, type II NKT cells seem to recognize diverse antigens presented by CD1d and given that these cells seem to be more abundant than type I NKT cells in humans, it is important to understand their roles and therapeutic potential.


References

{{reflist Immune system Cells