As apparent by the many biological functions it serves, apoptosis is essential for the overall livelihood of multi-cellular organisms. In the immune system, apoptosis plays a role in development, the elimination of infected and dysfunctional body cells, initiation of innate and adaptive immune responses, and much more. The goal of this page is to help explain connections between cell-mediated immunity and apoptosis during infection by an intracellular agent, such as a virus. Since apoptosis is an integral part of many cell pathways, it is important to understand how apoptosis interplays with different cellular and body processes. Cell-mediated immunity is one such process that is heavily influenced by programmed cell death.
Apoptosis in Cell-Mediated Immunity
A basic definition of cell-mediated immunity is antibody-independent mechanisms involving activation of natural killer cells (NKs), antigen-specific cytotoxic T cells, antigen presenting cells, and the release of interferons (IFN) in response to an antigen from invading intracellular pathogens. It is important to understand the aforementioned immune cells and their general functions so that we can view the later-presented mechanisms in the correct biological context.
Natural killer cells are a part of the body's innate immune system, meaning they are non-specific in nature and recognize cells based on whether or not they are presenting self-antigens. If the cell in question is not expressing a self-antigen on its surface alongside a major histocompatibility complex (MHC) class 1, which is often the case in early viral infection, the cell is signaled to undergo apoptosis through the release of pore forming proteins (perforins) and serine-proteases called granzymes. The interaction between natural killer cells and body cells is portrayed in Figure 1.
Figure 1
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Antigen-presenting cells (APCs) are a vital part of cell-mediated immunity, as they process endocytosed foreign antigens and present them on the cell surface along with an MHC molecule which can be recognized by various T cells. Two important APCs are dendritic cells and macrophages. Dendritic cells are the most important in regards to presenting antigens to cytotoxic and helper T cells. The general process of processing and presenting foreign antigens is shown in Figure 2 below along with the binding of T-cell receptors to MHC class 1.
Figure 2
http://www.nature.com/nri/journal/v3/n12/images/nri1250-f1.jpg
T cells with CD8 glycoproteins present on their surface are known as cytotoxic T cells. Cytotoxic T cells differentiate into active cytotoxic T lymphocytes (CTLs) when exposed to a foreign antigen presented by an APC along with MHC class 1. Costimulatory factors such as helper T cells and interferons also participate in differentiating cytotoxic T cells. If APCs are the "judge" of foreign antigens, cytotoxic T lymphocytes are the "executioners" of cells infected with intracellular pathogens. CTLs recognize and kill cells that are considered non-self due to presentation of foreign antigen. Although CTLs use perforins and granzymes like natural killer cells, they are different in the fact that CTL interaction with other cells is specific to a certain antigen depending on the initial antigen recognition event. Figure 3 below shows the interaction of a CTL with a virus-infected cell.
Figure 3
http://faculty.ccbcmd.edu/~gkaiser/SoftChalk%20BIOL%20230/Adaptive%20Immunity/CTLs/CTL_kill_caspase.jpg
Two types of granzymes are released from the CTL into the target cell: granzyme A and granzyme B. Granzyme B induces apoptosis through two pathways: a caspase-dependent pathway which is initiated by the cleaving of caspase 3, and a caspase independent pathway which acts by disrupting mitochondrial membrane potential and releasing apoptogenic factors into the cytoplasm. The full pathway is demonstrated below in Figure 4.
Figure 4
http://www.nature.com/nri/journal/v3/n5/images/nri1083-f2.gif
Granzyme A is actually the most abundant serine protease in the granules present in cytotoxic cells. Rather recently, it was elucidated that granzyme A activates a novel apoptosis pathway which functions by cleaving a site in the electron transport complex I. The end result of this is the disruption of mitochondrial function and the increase of reactive oxygen species (ROS) which in turn increases DNA damage and triggers apoptosis. Further information regarding this subject can be found in the following link.
CTLs also express Fas ligand (FasL) which allows them to induce cell death in a Fas-mediated pathway. This is briefly discussed in another section of the website and is depicted below in Figure 5.
Figure 5
http://faculty.ccbcmd.edu/~gkaiser/SoftChalk%20BIOL%20230/Adaptive%20Immunity/CTLs/fas_fasL_il.jpg
Perhaps the most important component of cell-mediated immunity are the cytokine molecules, interferons (IFN). The most important interferons in regard to apoptosis are type 1 interferons (IFN-1). These include interferon alpha and interferon beta which are commonly referred to as the "viral" IFNs because of their role in viral immunity. IFN-1 can be produced by all nucleated cells and are pleiotropic in function. Some of these functions include increasing the expression of MHC class 1, activating natural killer cells, increasing the activity of APCs, aiding in the proliferation of cytotoxic T cells, and ultimately inducing the apoptosis of virus-infected cells. Expression of IFN-1 and other cytokine genes is regulated through an intracellular mechanism which is activated by proteins known as pattern recognition receptors (PRR). True to their name, PRRs are able to recognize specific molecular patterns present in certain microorganisms. Some examples include viral nucleic acids and viral intermediate proteins. There are three known types of PRRs: toll-like receptors (TLR), RIG-1-like receptors (RLR), and NLRs. This conversation will briefly describe the mechanisms associated with the TLR and RLR-dependent recognition of viral nucleic acids, as not much is known about the NLR pathway.
Endosomal TLRs
Endosomal TLRs in dendritic cells are essential for the identification nucleic acids as well as the eventual production of IFN-1. They originate in the endoplasmic reticulum of dendritic cells and are exported to the cytoplasm inside an endosome through a currently undescribed mechanism. Three important endosomal TLRs that we will shortly discuss are TLR9, TLR3, and TLR7. TLR7 and TLR3 both recognize viral RNA (different types of vRNA). TLR7 specifically, complexes with myeloid differentiation factor 88 (MyD88) to form a complex with several interleukin-1-receptor-associated kinases (IRAK) and multiple tumor necrosis factor-receptor associated factors (TRAF). Formation of this complex activates interferon regulatory factor-7 (IRF-7) and nuclear factor-kappa B (NF-kB) which results in the production of IFN-1 and other cytokines. TLR3 complexes with multiple TRAFs as well as RIP-1. Much like TLR7, TLR3 activation results in activation of NF-kB and interferon regulatory factors. TLR9 acts in a nearly identical pathway as TLR7, and is shown in Figure 7. The main difference is that TLR9 detects double-stranded viral DNA instead of viral RNA.
Cytoplasmic RLRs
RLRs detect different types of viral RNA through RNA helicase activity. The two RLRs of interests are retinoic acid inducible gene 1 (RIG-1) and melanoma differentiation-associated gene 5 (MDA5). RIG-1 identifies single-stranded RNA and short double-stranded RNA while MDA5 primarily identifies long double-stranded RNA. Both cytoplasmic sensors are present in dendritic cells, macrophages, and fibroblasts. Both types of RLRs contain terminal caspase recruitment domains (CARDs) which initiate signaling pathways that result in the production of IFN-1 and the activation of Fas-associated death domain containing protein (FADD). FADD cleaves caspases 8 and 10 which results in the apoptosis of the effected cell. Before the cell dies, however, released IFN-1 activates natural killer cells and CTLs, and allow neighboring cells to make antiviral proteins (AVPs) which interfere with viral replication. The mechanism can be visualized below in Figure 6.
Perhaps the most important component of cell-mediated immunity are the cytokine molecules, interferons (IFN). The most important interferons in regard to apoptosis are type 1 interferons (IFN-1). These include interferon alpha and interferon beta which are commonly referred to as the "viral" IFNs because of their role in viral immunity. IFN-1 can be produced by all nucleated cells and are pleiotropic in function. Some of these functions include increasing the expression of MHC class 1, activating natural killer cells, increasing the activity of APCs, aiding in the proliferation of cytotoxic T cells, and ultimately inducing the apoptosis of virus-infected cells. Expression of IFN-1 and other cytokine genes is regulated through an intracellular mechanism which is activated by proteins known as pattern recognition receptors (PRR). True to their name, PRRs are able to recognize specific molecular patterns present in certain microorganisms. Some examples include viral nucleic acids and viral intermediate proteins. There are three known types of PRRs: toll-like receptors (TLR), RIG-1-like receptors (RLR), and NLRs. This conversation will briefly describe the mechanisms associated with the TLR and RLR-dependent recognition of viral nucleic acids, as not much is known about the NLR pathway.
Endosomal TLRs
Endosomal TLRs in dendritic cells are essential for the identification nucleic acids as well as the eventual production of IFN-1. They originate in the endoplasmic reticulum of dendritic cells and are exported to the cytoplasm inside an endosome through a currently undescribed mechanism. Three important endosomal TLRs that we will shortly discuss are TLR9, TLR3, and TLR7. TLR7 and TLR3 both recognize viral RNA (different types of vRNA). TLR7 specifically, complexes with myeloid differentiation factor 88 (MyD88) to form a complex with several interleukin-1-receptor-associated kinases (IRAK) and multiple tumor necrosis factor-receptor associated factors (TRAF). Formation of this complex activates interferon regulatory factor-7 (IRF-7) and nuclear factor-kappa B (NF-kB) which results in the production of IFN-1 and other cytokines. TLR3 complexes with multiple TRAFs as well as RIP-1. Much like TLR7, TLR3 activation results in activation of NF-kB and interferon regulatory factors. TLR9 acts in a nearly identical pathway as TLR7, and is shown in Figure 7. The main difference is that TLR9 detects double-stranded viral DNA instead of viral RNA.
Cytoplasmic RLRs
RLRs detect different types of viral RNA through RNA helicase activity. The two RLRs of interests are retinoic acid inducible gene 1 (RIG-1) and melanoma differentiation-associated gene 5 (MDA5). RIG-1 identifies single-stranded RNA and short double-stranded RNA while MDA5 primarily identifies long double-stranded RNA. Both cytoplasmic sensors are present in dendritic cells, macrophages, and fibroblasts. Both types of RLRs contain terminal caspase recruitment domains (CARDs) which initiate signaling pathways that result in the production of IFN-1 and the activation of Fas-associated death domain containing protein (FADD). FADD cleaves caspases 8 and 10 which results in the apoptosis of the effected cell. Before the cell dies, however, released IFN-1 activates natural killer cells and CTLs, and allow neighboring cells to make antiviral proteins (AVPs) which interfere with viral replication. The mechanism can be visualized below in Figure 6.
Figure 6
http://ars.els-cdn.com/content/image/1-s2.0-S1043466608002214-gr1.jpg
Figure 7
http://ars.els-cdn.com/content/image/1-s2.0-S1043466608002214-gr2.jpg
Conclusion
Conclusion
Apoptosis is an essential for the activity of a healthy and functional immune system. Pathways prior to apoptosis play a huge role in the activation of innate and adaptive immune responses, which both can result in the induced apoptosis of viral-infected cells. By inducing apoptosis through multiple death pathways cytotoxic cells can provide increased protection from intracellular parasites. Understanding the numerous different reasons for programmed cell death is just as important as understanding the intricacies of the canon apoptosis mechanism.
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