Cd1-restricted T cell

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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. [1]

Contents

In general, CD1-restricted T cells are divided according to their CD1 molecule. Humans express four CD1 isoforms divided in 2 groups: [2]

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. [2] CD1–restricted T cells produce TH1, IFN-γ and TNF-α 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. [3] Upon activation, they produce IFN-𝛾, IL-2, and IL-22, a cytokine with suspected roles in skin immunity. 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 (TH17) cells and recruit neutrophils. 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 lipid antigens, including glucose monomycolate (GMM) and free mycolic acid (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. [4] Germline-Encoded Mycolyl lipid reactive (GEM) T cells are defined by the expression of nearly invariant TRAV1-2/TRAJ9+ TCR α chains and CD4+. [5] 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. [6] LDN5-like cells show conservation in the TCR β chain outside the CDR3. [4]

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. [7]

CD1d-restricted NKT cells contribute to host defence by influencing the function of macrophages, dentritic cells, B cells and Natural Killer cells. They also contribute to tumor immunosurveillance and can mediate tumor rejection via interleukin 12 (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). [2] [8] 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 and CD86 and produce interleukin 12. [9] 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. [9]  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. [10] 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 of microbial and mammalian origin. They can also sense gene products of hepatitis B virus by detecting lysophosphatidylethanolamine generated through the cleavage of phosphatidylethanolamine 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. [9] 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.

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">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.

The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.

<span class="mw-page-title-main">T-cell receptor</span> Protein complex on the surface of T cells that recognises antigens

The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding between TCR and antigen peptides is of relatively low affinity and is degenerate: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.

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.

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">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.

<span class="mw-page-title-main">Antigen presentation</span> Vital immune process that is essential for T cell immune response triggering

Antigen presentation is a vital immune process that is essential for T cell immune response triggering. Because T cells recognize only fragmented antigens displayed on cell surfaces, antigen processing must occur before the antigen fragment, now bound to the major histocompatibility complex (MHC), is transported to the surface of the cell, a process known as presentation, where it can be recognized by a T-cell receptor. If there has been an infection with viruses or bacteria, the cell will present an endogenous or exogenous peptide fragment derived from the antigen by MHC molecules. There are two types of MHC molecules which differ in the behaviour of the antigens: MHC class I molecules (MHC-I) bind peptides from the cell cytosol, while peptides generated in the endocytic vesicles after internalisation are bound to MHC class II (MHC-II). Cellular membranes separate these two cellular environments - intracellular and extracellular. Each T cell can only recognize tens to hundreds of copies of a unique sequence of a single peptide among thousands of other peptides presented on the same cell, because an MHC molecule in one cell can bind to quite a large range of peptides. Predicting which antigens will be presented to the immune system by a certain MHC/HLA type is difficult, but the technology involved is improving.

Understanding of the antitumor immunity role of CD4+ T cells has grown substantially since the late 1990s. CD4+ T cells (mature T-helper cells) play an important role in modulating immune responses to pathogens and tumor cells, and are important in orchestrating overall immune responses.

In immunology, peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery. Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Peripheral tolerance prevents immune response to harmless food antigens and allergens, too.

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).

<span class="mw-page-title-main">Major histocompatibility complex, class I-related</span> Protein-coding gene in the species Homo sapiens

Major histocompatibility complex class I-related gene protein (MR1) is a non-classical MHC class I protein, that binds vitamine metabolites produced in certain types of bacteria. MR1 interacts with mucosal associated invariant T cells (MAIT).

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. Natural killer T cells should neither be confused with natural killer cells nor killer T cells.

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.

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.

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.

<span class="mw-page-title-main">CD1b</span> Mammalian protein found in Homo sapiens

T-cell surface glycoprotein CD1b is a protein that in humans is encoded by the CD1B gene.

Virtual memory T cells(TVM) are a subtype of T lymphocytes. These are cells that have a memory phenotype but have not been exposed to a foreign antigen. They are classified as memory cells but do not have an obvious memory function. They were first observed and described in 2009. The name comes from a computerized "virtual memory" that describes a working memory based on an alternative use of an existing space.

Group 1 CD1-restricted T cells are a heterogeneous group of unconventional T cells defined by their ability to recognize antigens bound on group 1 CD1 molecules with their TCR. Natural killer T (NKT) cells are a similar population with affinity to CD1d. Both groups recognize lipid antigens in contrast to the conventional peptide antigens presented on MHC class 1 and 2 proteins. Most identified T-cells that bind group 1 CD1 proteins are αβ T cells and some are γδ T cells. Both foreign and endogenous lipid antigens activate these cells.

References

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