Analysis Of Cytotoxic T Cells ( Ctcs )

a. This function is mediated by T cells and B cells (memory cells) in our body via adaptive immunity. The adaptive immune system evolved in early vertebrates and allows for a stronger immune response as well as immunological memory, where each pathogen is “remembered” by a signature antigen. The adaptive immune response is antigen-specific and requires the recognition of specific “non-self” antigens during a process called antigen presentation. Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is maintained in the body by memory cells. Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it. So basically killer T cells will identify antigens present on foreign cells. These antigens are not found in any of the cells inside our body. Therefore, T cells will identify them and kill them.

Cytotoxic T cells have receptors that allow them to connect with specific antigens and kill them to prevent an immune response to a virus. T helper cells have a surface protein called CD4 which aids in cell interaction and the secretion of cytokines.

Allison hypothesized that “if the CTLA-4 molecular brake could be temporarily disabled, the immune system would be able to launch a more vigorous attack on cancer cells, resulting in the shrinkage of tumors. ” From this hypothesis, Allison and his colleagues set out to test the theory by delivering a synthetically developed antibody that obstructs CTLA-4 activity to mice. Wolchok did not identify a research question of hypothesis for the studies involving a second immune system-braking molecule known as PD-1, which is a molecule on the surface of many T cells that initiates self-destruction of a cell after coming in contact with cancer cells. Other than the hypothesize provided by James Allison, Wolchok does not provide other specific hypothesis or research questions that are intended to be

this occurs in a series of steps, the first of which is incorporation of unidentified antigens by APCs in the epidermis and dermis. This process involves binding of the antigens to the MHC on the APC surface and the APC migrates to the lymph nodes. There, the APC binds reversibly and briefly with naïve or resting T cells through interactions between surface molecules located on both cells. Next, the MHC presents the antigen to a T lymphocyte receptor to begin activation of the T lymphocyte. The second signal for T lymphocyte activation is a non-antigen/ cell-cell interaction known as costimulation. If costimulation does not occur, the T lymphocyte will either undergo apoptosis or become unresponsive. Costimulation involves pairing of receptor with ligand on the T cell; these pairs include (LFA)-3 interacting with CD2, B7 interacting with CD28, and ICAM-1 interacting with LFA-1 (Lebwohl, 2003).

Immunology basically involves understanding the immune system and how it responds to various disease conditions. the immune system consists of a number of components. Traditionally, it is divided into humoral and cellular immune responses. It can also be distinguished into innate and adaptive immunity. The innate immunity can discriminate between normal tissues , self and newly encountered non-self-proteins while the adaptive immunity is the more complex system aimed at the eradication of intracellular pathogens. To do this, antigen derived from such pathogens that are often new to the host organism, need to be recognised by receptor-bearing specialised immune cells which respond to a complex system of stimulatory and costimulatory signals. Better understanding of the human immune system has led to the identification of a number of tumor-associated antigens in the 1980s and the development of various immunotherapeutic approaches. In recent years, identification of the specific antigenic MHC class I epitopes, advancements in genetic engineering, gene delivery, and cell-based therapeutic approaches allowed development of the novel immunotherapeutics.

In the first process, NK cells recognize the target cell through its cell surface receptors. Here the infected cells coated with immunoglobulin G (IgG) antibodies bind to the IgG specific receptors (FcγR) expressed on the surface of NK cells. This receptor-ligand interaction activates the downstream signaling cascade of NK cells, which direct them to destroy the target cell by a process called antibody-dependent cellular cytotoxicity. The second mechanism of recognition relies on the expression of killer activating (KAR) and inhibiting receptors (KIR) expressed on its cell surface. These receptors recognize a range of different molecules present on the surface of nucleated cells and regulate the functional outcome of NK cells. Once the activating receptor is engaged, a “Kill” instruction is issued to NK cells, that in turn activates perforin and granzyme mediated cytolysis. The “kill” signal, conversely, can be overridden when the signal is sent from the inhibitory receptor, a mode typically exploited by viruses in the suppression of NK cell-mediated cytotoxicity (Delves and Roitt, 2000). Other immune cells such as eosinophils, basophils, and mast cells also make a major contribution to the first line of defense mechanism. Basophils and mast cells contain IgE specific cell surface receptors (FceR) and exhibit high affinity for pathogens coated with the IgE antibodies. These cells are particularly important in the case of atopic allergies such as asthma and hay fever, wherein the allergen binds to IgE cross-links FceR and triggers the secretion of inflammatory mediators such as histamines and prostaglandins. Eosinophils, on the other hand, act as weak phagocytic cells and function mainly through the release of cationic proteins and reactive oxygen species (ROS) into the extracellular fluid. Collectively, these immune cells stimulate a rapid and

The major innate immune cell is the dendritic cell and the major adaptive immune cell is the T-cell. An innate cell is a cell that is always active and is not specific to an antigen. An adaptive cell circulates in the body in a naïve form until it is stimulated by a specific antigen. When the naïve cell becomes stimulated it turns into an effector cell that is specific to the antigen that stimulated it. Each of these cells have a specific function in the immune system and in graft rejection. The dendritic cell is important in recognizing MHC because it is a professional antigen presenting cell. This means that it will take up a part of the foreign MHC and display it within its own MHC. It is able to do this because there are two types of MHC. MHC class I displays proteins that are created within the cell, while MHC class II can display proteins from other cells that are phagocytosed (engulfed) by an antigen presenting cell. When a dendritic cell phagocytoses part of the foreign MHC and displays it on its own MHC class II it travels to a lymph node in the body and shows it to a T-cell’s receptor (TCR). This is the 1st signal required to stimulate a T-cell. The second signal occurs when CD28 on the T-cell binds to B7 on the antigen presenting cell. A dendritic cell is a professional antigen presenting cell because when it travels to the lymph node with the foreign antigen it increases the amount of

Helper T-cells (CD4+) interact with antigen fragments of MHC 2 class molecules on the surface of antigen presenting cells and when activated secrete cytokines that stimulate other lymphocytes. Cycotoxic T cells (CD8+) bind to MHC 1 class on infected host cells and secrete proteins that initiate destruction.

IFN-γ is a prototypic NK cell cytokine and its production within the cell influences the T helper 1 cells response, up regulates MHC class 1 expression on antigen presenting cells and activates macrophages while having antiproliferative effects on viral and transformed tumour cells (Caligiuri, 2008). Mature NK cells specialize against T cell elusive pathogens, this is mostly viruses. Most viruses evade cytotoxic T lymphocytes by downregulating the class I MHC in infected cells also seen in tumours, this prevents the presenting of derived viral proteins by the cell. However, by doing this it becomes susceptible to NK cell defenses. NK cells can become activated by many activation receptors however, they are inhibited by killer cell immunoglobulin-like receptors (KIRs). These are ligated by class I MHC. Activation receptors can directly recognize viral antigens which include natural cytotoxicity receptors which binds to viral hemagglutinin. Some viruses and tumours induce specific cell stress molecules that serve as ligands to NK activation receptors (Orange, 2013). This relationship between KIRs and activating receptors can be seen below in figure

The adaptive immune response is antigen-specific and requires the recognition of specific “non-self” antigens during a process called antigen presentation. Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is maintained in the body by "memory cells". Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it. so basically killer T cells will identify antigens present on foreign cells. These antigens are not found in any of the cells inside our body. So T cells will identify them and kill them.

Cancer is defined as a category of diseases that consist of cells in the human body dividing at an unstoppable rate and result in spreading to surrounding tissue creating tumors. Cancer affects approximately 14 million people and result in 8.2 million deaths as of 2012. However, researches continue to try and develop many kinds of treatments for cancer patients and aim to find a cure for this monstrous disease. Immunotherapy is one of the treatment options that involve the use of chimeric antigen receptors (CAR) T-cells to attack and destroy the cancer cells. The process of Immunotherapy began in 1976 as a method to create a vaccine using cowpox to prevent smallpox. However, the use of immunotherapy as a treatment for cancer patients began

Thus, the identification of CTL-epitopes and antigens is a major effort in translational immunology which can aid in the design of effective T-cell vaccines, immunotherapies, and immune monitoring of many malignancies (Ott et al., 2017; Schumacher & Schreiber, 2015; Tran et al., 2016).

3.1. T cells- Targeting infected or transformed cells in an inflammatory milieu is a complex and multifactorial process. To mediate their effector functions, primed CD8+ and CD4+ T cells need to migrate into the inflamed organs and initiate adaptive immune responses. After homing into the inflamed tissue, T cells require presentation of the cognate antigen-MHC complex on the surface of the target cells before effector functions can be initiated. In case of T cells, the identification and neutralisation of these target cells can be challenging, as the number of target cells in most cases is much lower than the tissue resident and/or inflammatory immune cells within the milieu. Moreover, successful initiation of effector T cell function results in lower abundance of target cells therefore T cells need to scan larger regions within the tissue for increasingly rare target cells. Similarly, the complex inflammatory environment presents several other challenges that may impede successful navigation of effector T cells like the presence of various chemotactic cues, pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) and alterations in the extracellular matrix (ECM).

Type II NKT TCRs are more prevalent in humans, yet, remain as one of the least functionally characterized NKT cell populations. However, with the advent of Jα18 gene KO studies, the role of type II NKT cells in antimicrobial immunity is progressively appreciated. A series of structural studies have provided the molecular basis of type I NKT TCR-mCD1d-Ag complex and demonstrated a distinct recognition pattern dominated by the CDR loops encoded by the germline region of the TCR. The parallel docking mode that underpinned type I NKT TCR recognition has remained well preserved regardless of the antigens or TCR Vβ gene usage and indicated the central role played by the invariant α-chain in innate-like recognition. Recently, the structure of the

Vaccines interact with three main cell types after an infection: macrophages, T lymphocytes, and B lymphocytes/antibodies (Understanding How Vaccines Work, 2013). The macrophages are the white blood cells that attack and consume the pathogen (Understanding How Vaccines Work, 2013). They leave behind parts of the pathogen, which are known as antigens (Understanding How Vaccines Work, 2013). The when the body comes in contact with the antigen, it recognizes that it is foreign body and that it is dangerous, it signals a response to attack it (Understanding How Vaccines Work, 2013). The antibodies are the cell that attack the antigen left by the macrophages (Understanding How Vaccines Work, 2013). The antibodies are produced by B lymphocytes, and the B lymphocytes are a type of defensive white blood cell (Understanding How Vaccines Work, 2013). The T lymphocytes are another type of defensive white blood cell (Understanding How Vaccines Work, 2013). They attack cells that have already been infected with a pathogen (Understanding How Vaccines Work, 2013). Without these three main cell types, a person would have no chance to fight off an