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The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as cancer cells, parasitic worms, and also objects such as wood splinters, distinguishing them from the organism's own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.
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.
Natural killer cells, also known as NK cells, are a type of cytotoxic lymphocyte critical to the innate immune system. They are a kind of large granular lymphocytes (LGL), and 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 cells, stressed cells, tumor cells, and other intracellular pathogens based on signals from several activating and inhibitory receptors. Most immune cells detect the antigen presented on major histocompatibility complex I (MHC-I) on infected cell surfaces, but NK cells can 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 I. 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.
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.
Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.
The innate immune system or nonspecific immune system is one of the two main immunity strategies in vertebrates. The innate immune system is an alternate defense strategy and is the dominant immune system response found in plants, fungi, prokaryotes, and invertebrates.
Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system kills a target cell, whose membrane-surface antigens have been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune response, can act to limit and contain infection.
Killer-cell immunoglobulin-like receptors (KIRs), are a family of type I transmembrane glycoproteins expressed on the plasma membrane of natural killer (NK) cells and a minority of T cells. In humans, they are encoded in the leukocyte receptor complex (LRC) on chromosome 19q13.4; the KIR region is approximately 150 kilobases and contains 14 loci, including 7 protein-coding genes and 2 pseudogenes.
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.
Ly49 is a family of membrane C-type lectin-like receptors expressed mainly on NK cells but also on other immune cells. Their primary role is to bind MHC-I molecules to distinguish between self healthy cells and infected or altered cells. Ly49 family is coded by Klra gene cluster and include genes for both inhibitory and activating paired receptors, but most of them are inhibitory. Inhibitory Ly49 receptors play a role in the recognition of self cells and thus maintain self-tolerance and prevent autoimmunity by suppressing NK cell activation. On the other hand, activating receptors recognise ligands from cancer or viral infected cells and are used when cells lack or have abnormal expression of MHC-I molecules, which activate cytokine production and cytotoxic activity of NK and immune cells.
NKG2 also known as CD159 is a receptor for natural killer cells. There are 7 NKG2 types: A, B, C, D, E, F and H. NKG2D is an activating receptor on the NK cell surface. NKG2A dimerizes with CD94 to make an inhibitory receptor (CD94/NKG2).
MHC class I polypeptide–related sequence A (MICA) is a highly polymorphic cell surface glycoprotein encoded by the MICA gene located within MHC locus. MICA is related to MHC class I and it has similar domain structure, however, it is not associated with β2-microglobulin nor binds peptides as conventional MHC class I molecules do. MICA rather functions as a stress-induced ligand (as a danger signal) for integral membrane protein receptor NKG2D ("natural-killer group 2, member D"). MICA is broadly recognized by NK cells, γδ T cells, and CD8+ αβ T cells which carry NKG2D receptor on their cell surface and which are activated via this interaction.
Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.
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. Their highest abundance is in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).
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.
UL16 binding protein 1 (ULBP1) is a cell surface glycoprotein encoded by ULBP1 gene located on the chromosome 6. ULBP1 is related to MHC class I molecules, but its gene maps outside the MHC locus. The domain structure of ULBP1 differs significantly from those of conventional MHC class I molecules. It does not contain the α3 domain and the transmembrane segment. ULBP1 is thus composed of only the α1α2 domain which is linked to the cell membrane by the GPI anchor. It functions as a stress-induced ligand for NKG2D receptor. ULBP1 is, for example, upregulated during HCMV infection. Binding of HCMV-encoded UL16 glycoprotein to ULBP1 interferes with cell surface localization of ULBP1; this represents another mechanism by which HCMV-infected cells might escape the immune system.
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.
Killer Activation Receptors (KARs) are receptors expressed on the plasma membrane of Natural Killer cells. KARs work together with Killer Inhibitory Receptors, which inactivate KARs in order to regulate the NK cells functions on hosted or transformed cells.These receptors have a broad binding specificity and are able to broadcast opposite signals. It is the balance between these competing signals that determines if the cytotoxic activity of the NK cell and apoptosis of distressed cell occurs.
NKG2D is an activating receptor (transmembrane protein) belonging to the NKG2 family of C-type lectin-like receptors. NKG2D is encoded by KLRK1 (killer cell lectin like receptor K1) gene which is located in the NK-gene complex (NKC) situated on chromosome 6 in mice and chromosome 12 in humans. In mice, it is expressed by NK cells, NK1.1+ T cells, γδ T cells, activated CD8+ αβ T cells and activated macrophages. In humans, it is expressed by NK cells, γδ T cells and CD8+ αβ T cells. NKG2D recognizes induced-self proteins from MIC and RAET1/ULBP families which appear on the surface of stressed, malignant transformed, and infected cells.
CD94/NKG2 is a family of C-type lectin receptors which are expressed predominantly on the surface of NK cells and a subset of CD8+ T-lymphocyte. These receptors stimulate or inhibit cytotoxic activity of NK cells, therefore they are divided into activating and inhibitory receptors according to their function. CD94/NKG2 recognize nonclassical MHC glycoproteins class I (HLA-E in human and Qa-1 molecules in the mouse).
References
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- ↑ Born, Willi K; M Kemal Aydintug; Rebecca L O'Brien (January 2013). "Diversity of γδ T-cell antigens". Cellular & Molecular Immunology. 10 (1): 13–20. doi:10.1038/cmi.2012.45. ISSN 2042-0226. PMC 4003174 . PMID 23085946.
- ↑ Eissmann, Philipp; J Henry Evans; Maryam Mehrabi; Emma L Rose; Shlomo Nedvetzki; Daniel M Davis (2010-06-15). "Multiple mechanisms downstream of TLR-4 stimulation allow expression of NKG2D ligands to facilitate macrophage/NK cell crosstalk". Journal of Immunology. 184 (12): 6901–6909. doi: 10.4049/jimmunol.0903985 . ISSN 1550-6606. PMID 20488792.
- ↑ Fernández-Messina, Lola; Hugh T Reyburn; Mar Valés-Gómez (2012). "Human NKG2D-ligands: cell biology strategies to ensure immune recognition". Frontiers in Immunology. 3: 299. doi: 10.3389/fimmu.2012.00299 . ISSN 1664-3224. PMC 3457034 . PMID 23056001.
- ↑ Arnon TI, Achdout H, Lieberman N, Gazit R, Gonen-Gross T, Katz G, Bar-Ilan A, Bloushtain N, Lev M, Joseph A, Kedar E, Porgador A, Mandelboim O (2004-01-15). "The mechanisms controlling the recognition of tumor- and virus-infected cells by NKp46". Blood. 103 (2): 664–672. doi: 10.1182/blood-2003-05-1716 . ISSN 0006-4971. PMID 14504081.
- ↑ Hayakawa, Yoshihiro (June 2012). "Targeting NKG2D in tumor surveillance". Expert Opinion on Therapeutic Targets. 16 (6): 587–599. doi:10.1517/14728222.2012.681378. ISSN 1744-7631. PMID 22530569. S2CID 27953271.
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