Activation Induced Cell Death: An Immunological Process

5 July 2024

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Activation induced cell death (AICD) is key in immunology. It controls how long T cells live once they’re activated. This process is vital for keeping the immune system balanced and not too aggressive, which could cause autoimmune diseases. When special proteins called Fas receptors and Fas ligands meet, they start a chain reaction that ends in the death of the cell.¹ Knowing how AICD works can help scientists create better treatments for autoimmune diseases and make cancer immunotherapies stronger.

Key Takeaways

AICD is a crucial immunological mechanism that regulates the lifespan of activated T cells.
AICD plays a vital role in maintaining peripheral immune tolerance and preventing excessive immune responses that could lead to autoimmune diseases.
AICD is triggered by the interaction between Fas receptors and Fas ligands, leading to the activation of a caspase cascade and programmed cell death.
Understanding AICD mechanisms is crucial for developing therapies targeting autoimmune disorders and enhancing cancer immunotherapy.
Dysregulation of AICD can result in the development of autoimmune diseases.

What is Activation Induced Cell Death?

Definition and Overview

Activation induced cell death, or AICD, is a type of cell death. It happens in activated T lymphocytes.¹ The process starts when the T cell receptor gets stimulated often. This causes the T cells to make Fas ligand.

The Fas ligand then sticks to Fas receptors on the same or close T cells.¹ When this happens, a series of signals starts. It makes caspases active, which leads to cell death, called apoptosis.¹

Significance in the Immune System

AICD is essential for the immune system. It helps by removing T cells that could harm our own body.¹ This makes sure that our immune system doesn’t become too active. If it did, it might attack our own tissues, leading to diseases like autoimmune conditions.

This process is key in keeping a balance in the number of T cells.² It stops our immune response from causing damage or chronic swelling.

Key Aspects of AICD	Description
Definition	AICD is a form of programmed cell death that occurs in activated T lymphocytes.¹
Trigger	AICD is started when the T cell receptor is stimulated many times, leading to Fas ligand expression.¹
Mechanism	The process goes on when FasL binds to Fas receptors on T cells nearby or the same. This triggers a signaling chain, starting with caspase activation and ending in cell death.¹
Role in Immune System	AICD is vital in maintaining immune tolerance. It does this by getting rid of harmful T cells.¹ It also plays a part in T cell number balance.²

Mechanisms Behind Activation Induced Cell Death

Fas ligand binds to Fas receptor, causing Fas to change shape. This makes its inside part connect with FADD, a key protein. Together, they bring in procaspase 8, turning it into caspase 8. Now, the group is called death-inducing signaling complex (DISC)³. Caspase 8 then starts a chain reaction inside the cell, leading to apoptosis.

Role of Fas Receptors and Fas Ligands

Fas receptor and Fas ligand are vital in AICD. Fas ligand binding starts a series of events. It makes the Fas receptor group together and then join with FADD³.

Signaling Pathways Involved

This Fas-Fas ligand link starts a signal that causes cell death. It brings in FADD to start. Then, FADD turns on procaspase 8³. Active caspase 8 begins the caspase cascade. This results in the T cell’s death.

Formation of the Death-Inducing Signaling Complex

Fas ligand attaching to Fas receptor creates the death-inducing signaling complex (DISC). This complex includes Fas, FADD, and procaspase 8³. Procaspase 8 becomes caspase 8 in the DISC. Active caspase 8 then starts the caspase cascade, causing apoptosis in the cell.

activation induced cell death and T Cell Regulation

AICD (activation-induced cell death) is key in keeping our immune system in check. It removes self-reactive T cells that were triggered.¹ By doing this, it stops autoimmune diseases from forming.¹ AICD also makes sure our immune response stays in the right range. This way, it stops our body from hurting itself during an attack.¹

Maintaining Peripheral Immune Tolerance

Getting rid of the self-reactive T cells is crucial. It stops autoimmune diseases from starting.¹ This is how AICD keeps our immune system from attacking our own body.¹

Preventing Excessive Immune Responses

AICD is important for not overreacting. It makes sure our immune response level is just right.¹ This stops our body from being damaged during an attack.¹ By managing how long T cells stay active, AICD keeps our immune system balanced.

Transcriptional Regulation of Fas Ligand

The level of Fas ligand (FasL) expression depends mostly on transcription. NFAT is a key player, setting FasL levels higher when T cell receptors get stimulated. This is done by boosting proteins that respond early.⁴ Also, c-Myc and MAX, its partner, help adjust FasL expression. Lowering c-Myc can stop the effect of FasL on AICD. FasL is controlled by this complex mix of factors.⁴

Role of NFAT and T Cell Receptor Stimulation

NFAT stands at the front as a critical factor, firing up FasL when the TCR gets active. This link between TCR signaling and AICD starts because of NFAT. It’s essential for bringing FasL expression up.⁴

Involvement of c-Myc and MAX Heterodimers

c-Myc, along with its partner, MAX, also has a say in FasL’s regulation. c-Myc boosts FasL, and without it, FasL can’t push AICD. Keeping a fine tune between c-Myc and MAX levels is crucial for FasL’s action.⁴

Regulation by Interferon Regulatory Factors

IRFs join in on regulating FasL’s transcription. IRF1 and IRF2 directly attach to the FasL promoter to adjust its output. Their involvement adds a new layer to the intricate control of FasL. This shows how many factors shape FasL’s expression.⁴

Implications in Autoimmune Diseases

Tweaks in the activation-induced cell death (AICD) process might birth autoimmune diseases.⁵ Problems in the mechanisms of how cells die could kick off these conditions.⁵ When AICD goes awry, cells that attack our own body might stick around, causing illness.⁵

Potential Dysregulation of AICD

This messes with the natural process of getting rid of harmful cells.⁵ As a result, the body gets confused and starts to attack itself.⁵ This can lead to autoimmune diseases.⁵

Consequences of Impaired T Cell Deletion

When our body fails to remove bad T cells as it should, we can get autoimmune diseases.⁵ The way cells normally die, inside and outside the cell, is vital for a healthy immune response.⁵ If something goes wrong here, T cells that attack us can keep living, starting a harmful reaction.⁵

Activation Induced Cell Death in Other Lymphocytes

AICD isn’t just about T cells; B cells are involved, too.¹ When B cells are activated, those with Fas and FasL can self-destruct. They might also trigger the death of nearby B cells.⁶ This helps make sure B cell levels stay balanced and stops too many harmful B cells from forming. This could help prevent autoimmune diseases.

AICD in B Cells

The kicking off point for AICD in B lymphocytes is when their B cell receptors (BCR) connect with something.⁶ This interaction sets off many reactions, turning on important molecules like PLCγ, Ras, and PI3K.⁶ When BCRs link up with the mIgM part of the B cell receptor, it can mean the end for some immature B cells.⁶ In some lab tests with B-lymphoma cells, joining up mIgM kicks off a process leading to cell suicide.⁶

Scientists are still figuring out why baby B cells don’t survive the AICD signal as well as the bigger B cells.⁶ BCR interaction gets the Src family kinases going, and they’re key in telling the cell to switch off.⁶ After Blk awakens because of anti-IgM, what happens next isn’t fully clear in mouse B-lymphoma cells.⁶ The journey of the signal goes through proteins like PLCγ, Ras, and PI3K. They help transmit the final message to stop growing and start dying.⁶

The BCR also activates a protein called phospholipase Cγ (PLCγ). This leads to making things like IP3 and DAG, which are critical for the cell.⁶ Calcium inside the cell and the activation of PKC are crucial for the cell to start copying its DNA and grow.⁶ The exact place of PKC in AICD of baby B cells is still under scrutiny.⁶

Therapeutic Potential and Future Directions

AICD⁷ could be key in treating autoimmune diseases and boosting cancer immunotherapy. It might help fix the problem of self-reactive T cells sticking around in autoimmune diseases.⁷ And in cancer treatment, working on AICD could keep tumor-specific T cells more active and long-lasting.⁸

Targeting AICD Pathways in Autoimmune Disorders

When AICD isn’t working right, self-reactive T cells can survive, sparking autoimmune diseases.⁷ Figuring out how AICD works lets researchers look for ways to get rid of those dangerous T cells.⁸ This could open new doors in treating diseases like rheumatoid arthritis, lupus, and type 1 diabetes.

Modulating AICD for Cancer Immunotherapy

In cancer therapy, tweaking AICD shows a lot of promise.⁸ It could make tumor-fighting T cells last longer and work better.⁸ One way to do this is by avoiding early deletion of these helpful cells.⁷ Plus, mixing AICD changes with other treatments could bring even better results for cancer patients.⁷

Key Molecules and Proteins Involved

In AICD, key players are the Fas receptor, Fas ligand, FADD, and caspase cascade. The interaction of Fas ligand with Fas receptor kicks off a chain reaction. This leads to apoptosis in the target cell.⁹

Fas Receptor and Fas Ligand

The Fas receptor and its ligand, Fas ligand, are vital for AICD, too. When they bind on T cells, it starts the cell death process.⁹

FADD and Procaspase 8

When Fas ligand attaches to Fas receptor, FADD comes into play. And, FADD helps procaspase 8 ready itself to be an active caspase 8. This setup is crucial for AICD and is called DISC.¹⁰

Caspase Cascade

Once caspase 8 is activated, it starts the caspase cascade. This turns on a series of events that ends in apoptosis. Research stresses the importance of caspases in this process.¹⁰

Molecule/Protein	Role in AICD	Significance
Fas Receptor (CD95)	Binds to Fas ligand, triggering apoptotic signaling	Essential component of the AICD process⁹
Fas Ligand (CD95 ligand)	Interacts with Fas receptor, leading to DISC formation	Mediates the induction of apoptosis in activated T cells⁹
FADD	Adaptor protein that recruits procaspase 8 to the DISC	Crucial for the activation of the caspase cascade⁹
Procaspase 8	Undergoes self-activation within the DISC	Initiates the proteolytic caspase cascade¹⁰
Caspase Cascade	Series of proteolytic events leading to apoptosis	Ultimately responsible for the demolition of the target cell¹⁰

Experimental Models and Research Approaches

Scientists use many methods to understand AICD. They look at how T cells get activated and die in lab tests. This helps them see the role of certain cell interactions and the start of cell death, like through caspases.³ By also studying mice that are changed at the genetic level, researchers learn more about cell death in living organisms. This work tells us how AICD affects the body’s defense system and fights against itself sometimes. All these studies help us get a fuller picture of AICD and its part in keeping our immune system in check.

In Vitro Studies on T Cell Activation and Death

Breaking down how T cells activate and then die shows us a lot about AICD. Researchers have a set of tools they use, from lab dishes to special tests, to focus on processes like the Fas-FasL pathway and the start of cell death.³ Working in these controlled settings helps them really get into the details of AICD and how it’s controlled.

Animal Models for Investigating AICD

Animal studies are key alongside lab research to understand the real-life effects of AICD.³ Mice that are genetically changed, like the lpr mouse, have been crucial in showing us how cell death affects the body during infections. They’ve also helped study how the body keeps immune reactions in balance through AICD.³ Thanks to these mice and other models, we’ve learned a lot about how our bodies maintain order in the immune response, even through ways that might seem negative. This has greatly broadened our knowledge of AICD in the immune system.

Historical Perspective and Discoveries

The idea of activation-induced cell death (AICD) begins with AICD and apoptosis in the immune system.¹¹ Cells were thought not to die in the 19th century because tools like microscopes were not advanced.¹¹ But in the 1990s, studies showed the Fas-FasL interactions are key to kickstarting AICD. They also found that a caspase chain is important for cell death signals.¹² Apoptosis itself was spotted by Flemming in 1885 but was named by scientists in the 1960s.¹²

Ever since, scientists have been pulling back the layers on how AICD is controlled.¹² Work focused on special proteins, or transcription factors, that include NFAT, c-Myc, and interferon regulatory factors. These findings have really upgraded our AICD know-how and its role in keeping our immune system in check. Plus, it helps ward off illnesses caused by the immune system itself.

Big studies have also shed more light on the ways cells die.¹¹ Virchow noticed necrosis, a type of cell death, in 1855. He saw this during his close look at cells affected by inflammation.¹¹ Another key figure, Metchnikoff, saw cells eating dead ones in 1882. This showed us how the immune system helps clear out waste.¹¹ Then, a team in 1972 figured out and named apoptosis, a very important find in cell death research.¹¹

All these historic moments and discoveries paved the way for understanding AICD today. It’s a big deal in our immune system, stopping it from going haywire and causing diseases.

Activation Induced Cell Death in Context

Activation-induced cell death (AICD) is key in the immune system. It helps keep the balance by dealing with rogue cells. These cells are dangerous because they can lead to autoimmune diseases if left alone.⁴

AICD even shows potential in fighting cancer. By adjusting how long specific cells live, their fight against tumors can become stronger.³ Researchers are digging deep into AICD. They hope to find new ways to fight both autoimmune diseases and cancer with this knowledge.¹³

The study of AICD is still vibrant. Scientists are working hard to unlock its secrets. They believe this could revolutionize how we treat certain illnesses with the immune system’s help.³⁴¹³

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