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Types of Induced Cell Death

Updated on Aug 21, 2023

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During a potential infection, the immune system relies on accurate and robust cellular activation and expansion. The massive release of activated effector cells can lead to major inflammation. Although this inflammation is necessary to quell the potential infection, the immune system provides safeguards against uncontrolled inflammation to protect the host from damage. 

The immune system implements checkpoints and controls to manage the number of active T cells and inflammation during and after an immune response. These controls serve integral roles in the maintenance of body homeostasis. Among these is the natural elimination of unnecessary cells via apoptosis or programmed cell death. 

Apoptosis regulates many bodily mechanisms, such as typical cellular turnover and inflammation reduction. Specific protein molecules serve as “death factors” or binding molecules that induce apoptosis. 

Unregulated Cell Populations

Excessive cell growth can contribute to the development of many diseases, most commonly cancer. Uncontrolled cellular replication can lead to cancerous growth that becomes exponentially harder for T cells to overcome. In addition to the increased risk of disease due to unmitigated cell replication, too much inflammation can cause immense harm to the host’s normal cells. The body implements controls on these risk factors by eliminating overactive or auto-reactive T cells circulating within the body that are no longer necessary for an immune response. 

Cells undergo a cell cycle to replicate and expand. This cycle is regulated by checkpoints that dictate which portion of the cell cycle a cell will move into next. Most cells are “resting”, or G0, state. This state allows the cell to function within every cellular niche other than cell replication. Once a cell is ready to replicate, signaling factors indicating cell type necessity will introduce signal transduction through the body’s immune cells. 

Numerous extracellular molecules can initiate cellular expansion and apoptosis. During T cell activation and expansion, the T cell receptor (TCR) is bound to a unique antigen, along with cytokines and co-stimulatory molecules. After this activation, the binding of these components leads to a cascade of reactions, including programmed cell death. 

Restimulation-Induced Cell Death 

Post-activation, T cells will circulate the blood until reencountering their specific antigen. RICD, or restimulation-induced cell death, is an apoptotic pathway triggered in activated T cells following this re-engagement. RICD regulates immune responses through negative control of cell expansion, reducing overall harm to the host from inflammation. 

T cells that circulate after activation are susceptible to elimination via the body’s natural apoptotic functions. This is due to the upregulation of apoptosis-controlling surface receptors on activated T cells. As T cells expand, they encounter checkpoints that determine the size and duration of an immune response and reassess the necessity of every effector cell. RICD is a pathway that regulates this mechanism. 

RICD relies specifically on IL-2, or interleukin-2, to induce apoptosis in T cells that have reencountered their specific antigen. IL-2 is upregulated after activation and is present in high concentrations within the periphery after an infectious attack. IL-2’s high concentration increases the likelihood of interaction with activated T cells and induction of RICD. 

RICD can also be triggered by excess and remaining antigens circulating during an active immune response and can aid in the immune system’s ability to focus attacks and not launch initiatives from multiple T cells. RICD acts as an upper limit for activated T cells, triggering in instances when there is an abundance of circulating antigens meeting the threshold for apoptosis, and an additional high concentration of IL-2 signifying sufficient activation and expansion.

Early in its clinical discovery, RICD is also known as AICD or activation-induced cell death. Modern understanding shows that RICD occurs in the time after an exposure event, and in response to the restimulation or re-engagement of TCR. 

Cytokine Withdrawal-Induced Death (CWID)

Another self-regulating mechanism the immune system introduces to maintain cell population homeostasis is cytokine withdrawal-induced death. CWID takes place when IL-2 has diminished and the active portion of activation has ceased. During this time, cytokines are eliminated or reabsorbed in the blood, depriving TCR complexes of the necessary cytokine co-stimulation required for reactivation. 

After a potential infection has been eliminated, IL-2 and other proinflammatory cytokines will typically diminish in concentration. This decrease triggers the upregulation of apoptotic surface receptors on circulating T cells, subjecting them to elimination via RICD.

Clinical Impacts of Induced Cell Death

RICD and CWID During Cell Sample Preparation

RICD and CWID are natural phenomena that can occur during fluctuating IL-2 concentrations after an immune response. RICD and CWID work together to influence cells in the culturing process to die ex vivo, after artificial activation procedures, polluting the sample with cellular debris

Proper cell culture maintenance can ensure that cells replicate and grow evenly. Immunology studies have indicated that gene p53 plays an important role in cell death after activation and that an inhibitor of p53 could reduce RICD and CWID in clinically-prepared T cells.

Restimulation in Cell Therapy

Understanding RICD and restimulation is increasingly important to developing treatments and our comprehensive knowledge of immune diseases. Gaining insight into the mechanisms of RICD can help elucidate how T cells play a role in lymphocyte-driven disorders, such as autoimmune disorders, lymphomas, and immune dysregulation. 

Only T cells that have been previously activated and circulate the peripheral blood are subject to restimulation events and RICD. Re-encountering a corresponding antigen influences nearby effector cells to respond, dictating the formation of memory T cells. Further understanding this trigger can provide strategies for clinical management of T cell effector reaction.

Akadeum’s Cell Separation and Activation Technology

Clearing dead cells and the associated debris and resolving wreaked cultured samples by RICD and CWID can be a cumbersome process. Using Akadeum’s culturing and expansion protocol increases the purity of the cultured sample, improving conditions downstream. 

Typical approaches to remedy the excess cell death require the use of harsh cell sorting magnets for debris removal, potentially causing more harm to the culture’s living cells. Akadeum offers simple and gentle cell separation and enrichment techniques using our Buoyancy Activated Cell Sorting (BACS™) microbubble technology, including Akadeum’s Dead Cell Removal Microbubble Kit

Utilizing gravity and natural buoyancy, Akadeum’s microbubble technology lifts unwanted cells from a solution, allowing for easy removal via pipetting or separation tubes. The pure solution of desired cells remains ready for downstream applications into activation and expansion protocols. 

Contact Akadeum today to discover how innovative microbubbles can revolutionize your workflows.

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