CD1

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CD1a molecule
Identifiers
Symbol CD1A
Alt. symbolsCD1
NCBI gene 909
HGNC 1634
OMIM 188370
RefSeq NM_001763
UniProt P06126
Other data
Locus Chr. 1 q22-q23
Search for
Structures Swiss-model
Domains InterPro
CD1b molecule
Identifiers
SymbolCD1B
Alt. symbolsCD1
NCBI gene 910
HGNC 1635
OMIM 188360
RefSeq NM_001764
UniProt P29016
Other data
Locus Chr. 1 q22-q23
Search for
Structures Swiss-model
Domains InterPro
CD1c molecule
Identifiers
SymbolCD1C
Alt. symbolsCD1
NCBI gene 911
HGNC 1636
OMIM 188340
RefSeq NM_001765
UniProt P29017
Other data
Locus Chr. 1 q22-q23
Search for
Structures Swiss-model
Domains InterPro
CD1d molecule
Identifiers
Symbol CD1D
NCBI gene 912
HGNC 1637
OMIM 188410
RefSeq NM_001766
UniProt P15813
Other data
Locus Chr. 1 q22-q23
Search for
Structures Swiss-model
Domains InterPro
CD1e molecule
Identifiers
Symbol CD1E
NCBI gene 913
HGNC 1638
OMIM 188411
RefSeq NM_030893
UniProt P15812
Other data
Locus Chr. 1 q22-q23
Search for
Structures Swiss-model
Domains InterPro

CD1 (cluster of differentiation 1) 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, from both endogenous and pathogenic proteins, to T cells and activate an immune response. Both αβ and γδ T cells recognise CD1 molecules. [1] [2]

Contents

The human CD1 gene cluster is located on chromosome 1. Genes of the CD1 family were first cloned in 1986, by Franco Calabi and C. Milstein, whereas the first known lipid antigen for CD1 was discovered in 1994, during studies of Mycobacterium tuberculosis. [3] The first antigen that was discovered to be able to bind CD1 and then be recognised by TCR is C80 mycolic acid. Even though their precise function is unknown, The CD1 system of lipid antigen recognition by TCR offers the prospect of discovering new approaches to therapy and developing immunomodulatory agents. [4] [1] [5] [2]

Types

CD1 glycoproteins can be classified primarily into two groups of CD1 isoforms which differ in their lipid anchoring, as well as their expression patterns of the CD1 genes (CD1d is constitutively expressed, whereas the group 1 CD1 genes are inducible and coordinately regulated by myeloid cells). [6]

CD1e is an intermediate form, a soluble lipid transfer protein that is expressed intracellularly. It does not present lipid antigens to T cells, rather plays a role in the processing of lipid antigens and loading them onto other CD1 molecules. [9] [10] [3]

In humans

Group 1

Group 1 CD1 molecules have been shown to present foreign lipid antigens, and specifically a number of mycobacterial cell wall components, to CD1-specific T cells.

Group 2

The natural antigens of group 2 CD1 are not well characterized, but a synthetic glycolipid, alpha-galactosylceramide (α-GalCer), originally isolated from a compound found in a marine sponge, has strong biologic activity.

Group 2 CD1 molecules activate a group of T cells, known as Natural killer T cells because of their expression of NK surface markers such as CD161. Natural Killer T (NKT) cells are activated by CD1d-presented antigens, and rapidly produce Th1 and Th2 cytokines, typically represented by interferon-gamma and IL-4 production.

The group 2 (CD1d) ligand α-GalCer is currently in phase I clinical trials for the treatment of advanced non-hematologic cancers.

Structure

CD1 proteins consist of a heavy chain with α1, α2, and α3 domains and a transmembrane domain which anchors it to the cell membrane. Much like the MHC molecules, the CD1 heavy chain associates with β2-microglobulin and its binding groove consists of two antiparallel α-helices, placed atop a β-sheet platform. The antigen-binding cleft architecture of CD1 proteins consists of A’, C’, F’ and T’ binding pockets and C’ and D’/E’ accessory portals, which act to accommodate the aliphatic hydrocarbon chains present in lipid, glycolipid, phospholipid, or lipopeptide antigens. CD1 antigen binding clefts are defined by locations of named portals where antigens protrude. [11] [9]

The main difference in structure between MHC and CD1 proteins is that in MHC proteins, the contact region for TCR show lateral symmetry, whereas human CD1 proteins show left-right asymmetry. Another difference between MHC and CD1 proteins is that the antigen display platform of CD1 molecules is smaller than the antigen display groove of MHC molecules. [3]

CD1-lipid TCR interactions

Human CD1 cells can recognise and bind a large number of lipids, from monoacylated lipids or lipopeptides to tetra-acylated lipids. However, not all of the lipid ligands can be considered antigens for T-cells. Free fatty acids sphingolipids, phospholipids, sulfolipids, lysophospholipids, amphipathic small molecules and some oils function as natural antigens for T cells. [1] [9]

10% of all αβ T lymphocytes in human peripheral blood are CD1-restricted T cells, out of which, the most abundant are the T cells specific for CD1c. Three models of CD1 recognition by TCR have been described: “head group recognition” model, “absence of interference” model and “altered CD1” model. The “head group recognition” model is considered to be a classical mode of CD1-antigen recognition, whereas the other two are only “emerging” CD1-antigen recognition models which predict that TCR contacts CD1 and not lipid. [11] [5] [1] [9]

Diagnostic relevance

CD1 antigens are expressed on cortical thymocytes, but not on mature T cells. This often remains true in neoplastic cells from these populations, so that the presence of CD1 antigens can be used in diagnostic immunohistochemistry to identify some thymomas and malignancies arising from T cell precursors. CD1a, in particular, is a specific marker for Langerhans cells, and can therefore also be used in the diagnosis of Langerhans cell histiocytosis. Other conditions that may show CD1 positivity include myeloid leukaemia and some B cell lymphomas. [12]

In cows and mice

Mice lack the group 1 CD1 molecules, and instead have 2 copies of CD1d. Thus, mice have been used extensively to characterize the role of CD1d and CD1d-dependent NKT cells in a variety of disease models.

It has recently been shown that cows lack the group 2 CD1 molecules, and have an expanded set of group 1 CD1 molecules. [13] Because of this and the fact that cows are a natural host of Mycobacterium bovis, a pathogen in humans as well, it is hoped that studying cows will yield insights into the group 1 CD1 antigen-presenting system.

Related Research Articles

<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.

<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">Major histocompatibility complex</span> Cell surface proteins, part of the acquired immune system

The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are called MHC molecules.

Antigen processing, or the cytosolic pathway, is an immunological process that prepares antigens for presentation to special cells of the immune system called T lymphocytes. It is considered to be a stage of antigen presentation pathways. This process involves two distinct pathways for processing of antigens from an organism's own (self) proteins or intracellular pathogens, or from phagocytosed pathogens ; subsequent presentation of these antigens on class I or class II major histocompatibility complex (MHC) molecules is dependent on which pathway is used. Both MHC class I and II are required to bind antigens before they are stably expressed on a cell surface. MHC I antigen presentation typically involves the endogenous pathway of antigen processing, and MHC II antigen presentation involves the exogenous pathway of antigen processing. Cross-presentation involves parts of the exogenous and the endogenous pathways but ultimately involves the latter portion of the endogenous pathway.

<span class="mw-page-title-main">Antigen-presenting cell</span> Cell that displays antigen bound by MHC proteins on its surface

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 using their T cell receptors (TCRs). APCs process antigens and present them to T cells.

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

Co-stimulation is a secondary signal which immune cells rely on to activate an immune response in the presence of an antigen-presenting cell. In the case of T cells, two stimuli are required to fully activate their immune response. During the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors.

<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.

MHC-restricted antigen recognition, or MHC restriction, refers to the fact that a T cell can interact with a self-major histocompatibility complex molecule and a foreign peptide bound to it, but will only respond to the antigen when it is bound to a particular MHC molecule.

A tetramer assay is a procedure that uses tetrameric proteins to detect and quantify T cells that are specific for a given antigen within a blood sample. The tetramers used in the assay are made up of four major histocompatibility complex (MHC) molecules, which are found on the surface of most cells in the body. MHC molecules present peptides to T-cells as a way to communicate the presence of viruses, bacteria, cancerous mutations, or other antigens in a cell. If a T-cell's receptor matches the peptide being presented by an MHC molecule, an immune response is triggered. Thus, MHC tetramers that are bioengineered to present a specific peptide can be used to find T-cells with receptors that match that peptide. The tetramers are labeled with a fluorophore, allowing tetramer-bound T-cells to be analyzed with flow cytometry. Quantification and sorting of T-cells by flow cytometry enables researchers to investigate immune response to viral infection and vaccine administration as well as functionality of antigen-specific T-cells. Generally, if a person's immune system has encountered a pathogen, the individual will possess T cells with specificity toward some peptide on that pathogen. Hence, if a tetramer stain specific for a pathogenic peptide results in a positive signal, this may indicate that the person's immune system has encountered and built a response to that pathogen.

<span class="mw-page-title-main">CD1E</span> Mammalian protein found in Homo sapiens

T-cell surface glycoprotein CD1e, membrane-associated is a protein that in humans is encoded by the CD1E gene.

<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).

<span class="mw-page-title-main">CD1A</span> Mammalian protein found in Homo sapiens

CD1a is a human protein encoded by the CD1A gene.

<span class="mw-page-title-main">Immunoglobulin C1-set domain</span>

C1-set domains are classical Ig-like domains resembling the antibody constant domain. C1-set domains are found almost exclusively in molecules involved in the immune system, such as in immunoglobulin light and heavy chains, in the major histocompatibility complex (MHC) class I and II complex molecules, and in various T-cell receptors.

Immunoevasins are proteins expressed by some viruses that enable the virus to evade immune recognition by interfering with MHC I complexes in the infected cell, therefore blocking the recognition of viral protein fragments by CD8+ cytotoxic T lymphocytes. Less frequently, MHC II antigen presentation and induced-self molecules may also be targeted. Some viral immunoevasins block peptide entry into the endoplasmic reticulum (ER) by targeting the TAP transporters. Immunoevasins are particularly abundant in viruses that are capable of establishing long-term infections of the host, such as herpesviruses.

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.

<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.

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.

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

  1. 1 2 3 4 Layre E, de Jong A, Moody DB (December 2014). "Human T cells use CD1 and MR1 to recognize lipids and small molecules". Current Opinion in Chemical Biology. Molecular immunology. 23: 31–38. doi:10.1016/j.cbpa.2014.09.007. PMID   25271021.
  2. 1 2 3 Tang Y, Ma S, Lin S, Wu Y, Chen S, Liu G, Ma L, Wang Z, Jiang L, Wang Y (2023-03-01). "Cell-free protein synthesis of CD1E and B2M protein and in vitro interaction". Protein Expression and Purification. 203: 106209. doi:10.1016/j.pep.2022.106209. ISSN   1046-5928. PMID   36460227. S2CID   254180046.
  3. 1 2 3 4 Van Rhijn I, Godfrey DI, Rossjohn J, Moody DB (October 2015). "Lipid and small-molecule display by CD1 and MR1". Nature Reviews. Immunology. 15 (10): 643–654. doi:10.1038/nri3889. PMC   6944187 . PMID   26388332.
  4. ↑ Porcelli S, Brenner MB, Greenstein JL, Balk SP, Terhorst C, Bleicher PA (October 1989). "Recognition of cluster of differentiation 1 antigens by human CD4-CD8-cytolytic T lymphocytes". Nature. 341 (6241): 447–450. Bibcode:1989Natur.341..447P. doi:10.1038/341447a0. PMID   2477705. S2CID   4264602.
  5. 1 2 3 4 5 Moody DB, Suliman S (2017-10-30). "CD1: From Molecules to Diseases". F1000Research. 6: 1909. doi: 10.12688/f1000research.12178.1 . PMC   5664979 . PMID   29152228.
  6. ↑ Zajonc DM, Wilson IA (2007). "Architecture of CD1 Proteins". T Cell Activation by CD1 and Lipid Antigens. Current Topics in Microbiology and Immunology. Vol. 314. pp. 27–50. doi:10.1007/978-3-540-69511-0_2. ISBN   978-3-540-69510-3. PMID   17593656.
  7. ↑ Sköld M, Behar SM (March 2005). "The role of group 1 and group 2 CD1-restricted T cells in microbial immunity". Microbes and Infection. 7 (3): 544–551. doi: 10.1016/j.micinf.2004.12.012 . PMID   15777730.
  8. ↑ Mori L, Lepore M, De Libero G (2016-05-20). "The Immunology of CD1- and MR1-Restricted T Cells". Annual Review of Immunology. 34 (1): 479–510. doi:10.1146/annurev-immunol-032414-112008. ISSN   0732-0582. PMID   26927205.
  9. 1 2 3 4 Zajonc DM (August 2016). "The CD1 family: serving lipid antigens to T cells since the Mesozoic era". Immunogenetics. 68 (8): 561–576. doi:10.1007/s00251-016-0931-0. ISSN   0093-7711. PMC   5087154 . PMID   27368414.
  10. ↑ Angenieux C, Salamero J, Fricker D, Cazenave JP, Goud B, Hanau D, de La Salle H (December 2000). "Characterization of CD1e, a third type of CD1 molecule expressed in dendritic cells". The Journal of Biological Chemistry. 275 (48): 37757–37764. doi: 10.1074/jbc.M007082200 . PMID   10948205.
  11. 1 2 3 4 5 Moody DB, Cotton RN (2017-06-01). "Four pathways of CD1 antigen presentation to T cells". Current Opinion in Immunology. Antigen processing * Special section: Metabolism of T cells. 46: 127–133. doi:10.1016/j.coi.2017.07.013. ISSN   0952-7915. PMC   5599164 . PMID   28756303.
  12. ↑ Kumarasen C, Anthony S-Y L (2003). Manual of diagnostic antibodies for immunohistology. London: Greenwich Medical Media. pp. 59–60. ISBN   1-84110-100-1.
  13. ↑ Van Rhijn I, Koets AP, Im JS, Piebes D, Reddington F, Besra GS, et al. (April 2006). "The bovine CD1 family contains group 1 CD1 proteins, but no functional CD1d". Journal of Immunology. 176 (8): 4888–4893. doi: 10.4049/jimmunol.176.8.4888 . PMID   16585584.
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