CD83 (Cluster of Differentiation 83) is a human protein encoded by the CD83 gene. [5]
CD83 (Cluster of Differentiation 83) is a human protein encoded by the CD83 gene. [5]
The membrane-bound form of CD83 consists of an extracellular V-type immunoglobulin-like domain, a transmembrane domain and a cytoplasmic signaling tail. A free soluble form consists of the immunoglobulin-like domain alone. Membrane-bound CD83 is expected to form trimers. Soluble CD83 is able to assemble into dodecameric complexes. [6]
The CD83 gene is located on human chromosome 6p23 and mouse chromosome 13. In humans, a promoter 261 bp upstream consists of five NF-κB and three interferon regulatory factor binding sites, reflecting the involvement of CD83 in inflammation, [7] as well as binding sites for the aryl hydrocarbon receptor. The latter also occur in an enhancer sequence located 185 bp downstream, inside the second intron, [8] and may suggest negative regulation of transcription by microbial metabolites produced in the gut.
The transmembrane domain of membrane-bound CD83 stabilizes MHC II, costimulatory molecules and CD28 in the membrane by antagonizing MARCH-family E3 ubiquitin ligases. [9] [10]
It is not clear what ligands interact with CD83, but membrane-bound CD83 may homotypically interact with the soluble form, suggesting autocrine immune regulation. [11] However, it contrasts with differences between the single expression of soluble CD83 on monocytes and membrane-bound CD83 on activated dendritic cells seems also as their good marker.[ clarification needed ] [12] Soluble CD83 also binds to CD154, leading to T helper type 2 lymphocyte apoptosis by suppression of Bcl-2 inhibitors. [13]
The development of thymocytes during the positive-selection stage may be guided by CD83 expression on cortical thymic epithelial cells (cTECs). CD4 + CD8 + double-positive thymocytes surrounded by specially differentiated cTECs called thymic nurse cells are tested for function of their αβ T cell receptor (TCR); a nonreactive TCR leads to thymocyte death by neglect. Successful rearrangement of a reactive TCR supports survival and restriction of expression to CD4 or CD8 alone on single-positive thymocytes, depending on the ability to recognize MHC II or MHC I, respectively. Upregulation of MHC II turnover on thymic nurse cells by CD83 may enlarge the population of CD4+ single-positive thymocytes. [14] [10]
T regulatory cells (Treg cells) are present in two major populations: thymically induced and peripherally induced Treg cells. All Treg cells express the Foxp3 transcription factor, establishing their suppressive phenotype. Foxp3 expression is not affected by loss of CD83 in a CD83 knockout mouse. In contrast, CD83 seems important for peripheral Treg cell induction, as suggested by reduction of this population in a conditional knockout mouse lacking CD83 specifically in Treg cells, which results in a proinflammatory phenotype. [15]
CD83 deficiency also results in an imbalances in effector function of Treg cells, as decreased expression of the T helper type 2 cell transcription factor GATA3 is also important for ST2 production. [16]
Activated Treg cells produce large amounts of soluble CD83, leading to downregulation of IRAK-1 at inflamed sites, downregulation of toll-like receptor signaling, and switching of inflammatory signals to tolerance establishment. [16]
CD83 expression is a marker for mature dendritic cells. [12] CD83 stabilizes MHC II on membrane by antagonizing MARCH E3 ubiquitin ligases. A MARCH1 knockout mouse shows accumulation of MHC II, which leads to reduced CD4 + T lymphocyte activation and reduced IL-12 production. [17] Conversely, a CD83 knockout mouse shows a reduction of MHC II and CD86, better response to bacterial infection, and higher production of IL-12 than in the wild type. CD83 seems to be an important regulator of dendritic cell phenotype and MHC II turnover, mediated by CD83-dependent endosome processing. [11]
CD83 expression correlates with rate of activation of B lymphocytes and it is under control of the B cell receptor, CD40, or Toll-like receptor activation, as in other lymphocytes, where CD83 is expressed upon stimulation. A CD83 knockout mouse shows upregulated proliferation of B lymphocytes, suggesting that CD83 acts as a brake on proliferation. [18] CD83 does not affect affinity maturation of antibodies, but its deficiency enhances immunoglobulin E class switching, suggesting that CD83 may be involved in allergy development and could be a therapeutic target for allergy treatment. [19]
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.
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.
In immunology, central tolerance is the process of eliminating any developing T or B lymphocytes that are autoreactive, i.e. reactive to the body itself. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides. Lymphocyte maturation occurs in primary lymphoid organs such as the bone marrow and the thymus. In mammals, B cells mature in the bone marrow and T cells mature in the thymus.
Immune tolerance, also known as immunological tolerance or immunotolerance, refers to the immune system's state of unresponsiveness to substances or tissues that would otherwise trigger an immune response. It arises from prior exposure to a specific antigen and contrasts the immune system's conventional role in eliminating foreign antigens. Depending on the site of induction, tolerance is categorized as either central tolerance, occurring in the thymus and bone marrow, or peripheral tolerance, taking place in other tissues and lymph nodes. Although the mechanisms establishing central and peripheral tolerance differ, their outcomes are analogous, ensuring immune system modulation.
Cluster of Differentiation 86 is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells, and on other antigen-presenting cells. Along with CD80, CD86 provides costimulatory signals necessary for T cell activation and survival. Depending on the ligand bound, CD86 can signal for self-regulation and cell-cell association, or for attenuation of regulation and cell-cell disassociation.
Chemokine ligand 1 (CCL1) is also known as small inducible cytokine A1 and I-309 in humans. CCL1 is a small glycoprotein that belongs to the CC chemokine family.
Chemokine ligand 21 (CCL21) is a small cytokine belonging to the CC chemokine family. This chemokine is also known as 6Ckine, exodus-2, and secondary lymphoid-tissue chemokine (SLC). CCL21 elicits its effects by binding to a cell surface chemokine receptor known as CCR7. The main function of CCL21 is to guide CCR7 expressing leukocytes to the secondary lymphoid organs, such as lymph nodes and Peyer´s patches.
Integrin, alpha E (ITGAE) also known as CD103 is an integrin protein that in human is encoded by the ITGAE gene. CD103 binds integrin beta 7 to form the complete heterodimeric integrin molecule αEβ7, which has no distinct name. The αEβ7 complex is often referred to as "CD103" though this strictly refers only to the αE chain. Note that the β7 subunit can bind with other integrin α chains, such as α4 (CD49d).
C-C chemokine receptor type 7 is a protein that in humans is encoded by the CCR7 gene. Two ligands have been identified for this receptor: the chemokines ligand 19 (CCL19/ELC) and ligand 21 (CCL21). The ligands have similar affinity for the receptor, though CCL19 has been shown to induce internalisation of CCR7 and desensitisation of the cell to CCL19/CCL21 signals. CCR7 is a transmembrane protein with 7 transmembrane domains, which is coupled with heterotrimeric G proteins, which transduce the signal downstream through various signalling cascades. The main function of the receptor is to guide immune cells to immune organs by detecting specific chemokines, which these tissues secrete.
CD69 is a human transmembrane C-Type lectin protein encoded by the CD69 gene. It is an early activation marker that is expressed in hematopoietic stem cells, T cells, and many other cell types in the immune system. It is also implicated in T cell differentiation as well as lymphocyte retention in lymphoid organs.
Lymphotoxin-beta (LT-beta) also known as tumor necrosis factor C (TNF-C) is a protein that in humans is encoded by the LTB gene.
Signaling lymphocytic activation molecule 1 is a protein that in humans is encoded by the SLAMF1 gene. Recently SLAMF1 has also been designated CD150.
Killer cell lectin-like receptor subfamily B, member 1, also known as KLRB1, NKR-P1A or CD161, is a human gene.
Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biological effects on T cell function but overall has an immune inhibitory effect. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.
OX-2 membrane glycoprotein, also named CD200 is a human protein encoded by the CD200 gene. CD200 gene is in human located on chromosome 3 in proximity to genes encoding other B7 proteins CD80/CD86. In mice CD200 gene is on chromosome 16.
Fibrinogen-like protein 2, also known as FGL2, is a protein which in humans is encoded by the FGL2 gene.
Hepatitis A virus cellular receptor 2 (HAVCR2), also known as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), is a protein that in humans is encoded by the HAVCR2 (TIM-3)gene. HAVCR2 was first described in 2002 as a cell surface molecule expressed on IFNγ producing CD4+ Th1 and CD8+ Tc1 cells. Later, the expression was detected in Th17 cells, regulatory T-cells, and innate immune cells. HAVCR2 receptor is a regulator of the immune response.
CD160 antigen is a protein that in humans is encoded by the CD160 gene.
CD8a, is a human gene.
Thymic epithelial cells (TECs) are specialized cells with high degree of anatomic, phenotypic and functional heterogeneity that are located in the outer layer (epithelium) of the thymic stroma. The thymus, as a primary lymphoid organ, mediates T cell development and maturation. The thymic microenvironment is established by TEC network filled with thymocytes in different developing stages. TECs and thymocytes are the most important components in the thymus, that are necessary for production of functionally competent T lymphocytes and self tolerance. Dysfunction of TECs causes several immunodeficiencies and autoimmune diseases.