The immune system is a complex system composed of multiple cell types at distinct locations throughout the body. Coordinating an effective immune response requires constant communication between the cells of the immune system so that each knows how to behave at any given time. A breakdown in communication, such as occurs if a signal is provided at an inappropriate time or is not shut off appropriately, can result in autoimmunity or immunopathology, respectively.
Cells of the immune system communicate by cell to cell contact and through the production of soluble factors that bind cognate receptors expressed at the surface of target cells.
B-cells The major function of B lymphocytes is to develop into antibody-secreting plasma cells following stimulation by foreign antigens of bacteria, viruses and tumor cells. Antibodies are specialized proteins that specifically recognize and bind to specific antigens that caused their stimulation. Antibody production and binding to foreign antigens is often critical as a means of signaling other cells to engulf, kill or remove that substance from the body.
T-cells T lymphocytes are usually divided into two major subsets that are functionally and phenotypically different. T helper (TH) cells, also called CD4+ T cells, are involved in coordination and regulation of immunological responses. They function to mediate responses by the secretion of lymphokines that stimulate or otherwise affect other cells involved in the immune responses.
Cytotoxic T lymphocytes ( Tc cells or CTLs) or CD8+ T cells.
These cells are involved in directly killing certain tumor cells, virus-infected cells, transplant cells, and sometimes eucaryotic parasites. CD8+ T cells are also important in down-regulation of immune responses.
Both types of T cells can be found throughout the body, most conspicuously in lymphoid organs (lymph nodes and spleen) but also the liver, lung, blood, and the intestinal tract.
Natural Killer cells Natural killer cells, known as NK cells, are similar to CTLs (CD8+ T cells). They function as effector cells that directly kill certain tumors such as melanomas, lymphomas and virus-infected cells, most notably herpes and cytomegalovirus-infected cells. However, NK cells, unlike the CD8+ (Tc) cells, kill their target cells without need for recognition of antigen in association with MHC molecules. NK cells that have been activated by secretions from CD4+ T cells will kill their tumor or viral-infected targets more effectively.
Macrophages Macrophages are important in the regulation of immune responses. Besides their role in phagocytosis, they may function as antigen-presenting cells (APCs) because they ingest foreign materials and present these antigens to other cells of the immune system such as T-cells and B-cells. This is one of the important first steps in the initiation of an immunological response. Macrophages, stimulated by certain lymphokines, exhibit increased levels of phagocytosis and are also secrete cytokines that modulate immune responses.
Dendritic cells Dendritic cells also originate in the bone marrow and function as antigen presenting cells (APCs). In fact, the dendritic cells are more efficient APCs than macrophages. These cells are usually found in structural compartments of the lymphoid organs such as the thymus, lymph nodes and spleen. However, they are also found in the bloodstream and other tissues of the body. It is believed that they capture and process antigens in lymphoid organs where an immunological response is initiated. Of particular interest is the recent finding that dendritic cells bind large numbers of HIV particles, and may be a reservoir of virus that is transmitted to CD4+ T cells.
In the mammalian immune system, many types of while blood cells with specific functions and responsibilities constantly work to defend the body against disease.
There are two types of immune cells that are at the center of the fight against cancer: natural killer (NK) cells and cytotoxic T cells.
NK cells are part of the innate immune response and survey the body for any unusual activity before signaling for additional help. If necessary, the activation of NK cells will then signal for a secondary response in which cytotoxic T cells are called to assist in the removal of the remaining unhealthy/cancerous cells. In this project, we will be referring to these cells as Killer Immune Cells. Both of these types of killer cells go through a similar process from detection to elimination of the cancer cell.
Killer immune cells scan the body for unhealthy cells, such as cancer. They do this by recognizing and binding specific markers (antigens) on the surface of cells. To be able to differentiate between healthy and cancer cells, killer immune cells use a variety of receptors that bind to specific antigens present in the target cell’s surface.
Once the receptors bind their respective antigens they send an activation or inhibitory signal to the inside of the cell.
The balance between activating and inhibitory signals tells the killer immune cell if it is in the presence of a cancer or healthy cell, respectively. If the activation signal predominates the killer immune cell will get ready to eliminate the cancer cell. In case the inhibitory signal is stronger the killer cell knows that it is in the presence of a healthy cell and it will move on to the next target.
When activating receptors in the killer cell bind cancer antigens they send the activating signal to the inside of the cell through an intracellular activation domain. This activation domain recruits and activates kinases, which in turn will activate other proteins and start a series of signaling cascade events that will lead to the formation of a tight junction between the killer cell and the cancer cell called an immune synapse.
Conversely, when an inhibitory receptor binds a normal antigen it will activate its intracellular inhibition domain, which will recruit phosphatases. The phosphatases erase the work of kinases and a killing response will not occur, letting the killer cell move on to check the health of other cells (see Figure 1).
Figure 1: Killer cells have a variety of receptors at their cell-surface that bind cancer antigens or normal antigens. The receptors that bind cancer antigens get activated, recruiting and activating kinases, which in turn activate signal cascades that lead to the killing of the cancer cell by the killer immune cell.
Receptors that bind normal antigens in the target cell will also get activated but instead they recruit and activate phosphatases, which will silence the action of kinases (Diagram on the right). In this case the killer cell spares the target cell and moves on to check the health of other cells.
2 – Immune Synapse Formation and Cytotoxic Granules Release
Once a killer cell is activated and an immune synapse is formed, the cytotoxic granules present in killer cells get released to act on the cancer cell (see Figure 2). These cytotoxic granules are rich in killing agents, such as granzymes, and once these agents penetrate the cancer cell membrane they will induce the cancer cell to apoptose (kill itself). The immune synapse, a tight embrace between the cancer and killer cell, limits the spread of the killer cell’s arsenal to neighboring, possibly healthy, cells.
After the killer cell receptor is activated by binding the cancer antigen (1) a series of signaling events lead to the formation of the immune synapse (2). By the time the killer cell is ready to kill the cytotoxic granules recruited to the synapse and released (3). Content from the cytotoxic granules, such as granzymes, acts on the cancer cell and leads the cancer cell to apoptose (4).