An Overview of Activation-Induced Cell Death
March 2023 Share
What Is Apoptosis?
Cell death is a natural and normal part of the human body’s maintenance mechanisms. Apoptosis means the steady process of programmed cell death that occurs to aid in the body’s growth and development.
Apoptosis regulates the life and death of cells, which affects several body processes like cell turnover, growth, immune functioning, hormone distribution, and hormone atrophy. Cell survival or death directly impacts the immune system’s population numbers of T cells, naive cells, and memory cells. Insight into the mechanisms of cell apoptosis is useful clinically and drives the goal to manipulate apoptosis ex vivo, which could greatly expand the treatment of diseases.
Although apoptosis can be a useful regulatory mechanism for maintaining cell populations, aberrant apoptosis can have disastrous effects and lead to health complications. Apoptosis occurring too often can lead to neurodegenerative diseases like Alzheimer’s and Parkinson’s. This is due to the excess number of neurotransmitting cells and neurons damaged from uncontrolled cell death.
Too infrequent a rate of apoptosis can cause issues like cancer, or unmitigated cell growth. Cancer evades checkpoint markers that initiate apoptosis in replicating cells and continuously moves through the cell division cycle.
Internally Programmed Apoptosis
Apoptosis is integral to the human immune system’s functionality. The elimination of activated T cells after an immune system attack mitigates the risk of uncontrolled inflammation.
Excess inflammation plays a part in nearly every major disease. Inflammation is a powerful force that, left unchecked, can cause significant damage to cellular DNA and populations. After cell expansion, differentiation, and proliferation, immune cells are genetically determined to begin apoptosis.
During apoptosis, cells will shrivel and distort in size, making them noticeably different in physical characteristics from living cells. Although their shape is contorted and internal components dissolved, the cytoplasm remains intact within the cell membrane until being destroyed by a macrophage or another engulfing cell.
Once more effector cells are needed, differentiation, activation, and expansion will begin again. This process is dictated by extracellular proteins and ligands that bind to receptors that modulate these processes. These receptors are up-regulated in expression following cell activation.
Artificial T Cell Activation
Many clinical treatments in cell therapies utilize cells that have been activated and expanded ex vivo, or in a lab. These cells are then returned to the patient via intravenous infusion to be adopted as their own. The activated cells launch an immune response and pathogen-killing initiatives at the target specified during lab expansion and eliminate the growth of the targeted cellular group.
It is difficult to accurately expand and activate T cells in the lab due to activation-induced cell death. These complications can make cell culture maintenance much more challenging. Increased rates of apoptosis in ex vivo expansions lead to cell clumping and poor cell culturing. Cells can be damaged by the process of cleaning clumping or removing debris from the solution.
What Is Activation-Induced Cell Death (AICD)?
While activating and expanding cell populations in the lab, it’s common to experience activation-induced cell death. This is caused by the natural apoptosis mechanism that lies genetically within effector cells.
Specifically, effector cells express Fas or a TNF (tumor necrosis factor) receptor, which binds to a death factor, such as Fas Ligand, a ceramide, or ROS (reactive oxygen species.) Directly following activation, the expression of Fas is upregulated, causing T cells to express Fas after binding to TCR. At this point, these effector cells could be triggered into activation-induced apoptosis by Fas Ligand, an apoptotic protein.
Cell therapies, such as CAR T cell therapies, and tumor-infiltrating cell therapies are more successful on smaller tumors. Large tumors have a high T cell demand from the body and require constant expansion and proliferation. Constant artificial stimulation of T cells can increase the rate at which Fas is upregulated, increasing the rate of AICD, or apoptosis.
Activation-Induced Cell Death T Cells
Fas and Fas Ligands are vital components of the overall mechanism controlling effector cell survival and death. The regulation, expression, and abundance of these receptors and proteins dictate the number of active effector cells in the body.
Properly functioning activation-induced cell death provides a necessary safeguard against uncontrolled T cell activation, proliferation, and inflammatory response. Too high a rate of any of these cellular phenomena can result in complications like cancer and autoimmune diseases.
IL-2 Activation-Induced Cell Death
IL-2, or interleukin-2, is a cytokine produced by multiple immune cells, such as T cells. IL-2 aids in the development of the immune system and increases the activity of T and B cells.
In addition to its part in activation and maturation, IL-2 also induces apoptosis in some late-stage effector cells. Playing a vital role in activation-induced cell death, IL-2 guides the elimination of self-reactive or auto-reactive T cells. This ability to initiate apoptosis in immune cells is considered proapoptotic. IL-2 is also responsible for diminishing memory effector cell count and increasing cell cycling.
What Are Applications of AICD?
Understanding more about AICD and the proteins that trigger immune cell death is crucial for advancing modern cellular therapies. Because AICD presents challenges to current approaches to tumor reduction, finding a clinical method of mitigating or pausing the onset of activation-induced cell death could potentially expand the abilities of the existing cellular treatments.
T cells are utilized as cellular material in numerous cell therapies, and therefore it is important to know how they live and die, and what components trigger T cells into apoptosis.
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