Understanding T Cell Exhaustion

What Is T Cell Exhaustion?

Exhaustion is a general term used to describe instances in an immune response when T cells develop a loss in functionality due to overstimulation. Exhausted T cells still exhibit some effector abilities but are significantly weakened. 

Exhaustion changes the physical attributes of T cells, inhibiting them and making them unable to release inflammation-driving cytokines. Although reversible, excessive T cell exhaustion can have significant short- and long-term effects on the immune system. 

The Effects of T Cell Exhaustion

When T cells are exhausted, they lose effector and cytotoxic T cell functionality and become ineffective at eliminating cancer cells. Too great a quantity of exhausted T cells can lead to the body becoming overcome with infection or permanently vulnerable to future infections. Exhaustion is very common in chronic diseases—such as HIV, Hep C, and cancer—for which T cells are in high demand to quell the ongoing spread of tumor cells or infection. 

Common T Cell Exhaustion Markers

T cells undergoing exhaustion experience genetic changes to their transcriptional mechanisms. These transcriptional changes result in a change in T cell phenotype and functionality. This exhaustion is not merely a state or transitory period of effector cell function, but a characteristic of a genetically distinct cell altered through exhaustion. This means exhausted T cells are distinct from effector T cells and other kinds of T cells due to the upregulation of many inhibitory surface markers.

Programmed death protein, PD-1, and other crucial negative regulatory markers like LAG-3 and TIM-3 are expressed in high quantities on the exhausted T cell’s surface, readying it to bind to an inhibitory ligand. This upregulation directly affects the exhausted T cell’s abilities. 

What Causes Immune System Exhaustion?

Broadly speaking, overstimulation or constant activation events can cause T cells to become exhausted. There are many situations in which a T cell could become exhausted, but it is always a result of chronic stimulation. T cell exhaustion commonly occurs in tumor locations, where naive T cells experience rapid activation and expansion. There’s a constant demand for repeated cell-killing due to a loss of control over the cancerous growth. 

T cell exhaustion is also a common challenge during cell production for modern cell therapies, such as CAR T-cell therapy. Due to the nature of CAR T-cell therapy, therapeutic T cells are required to kill and attack tumor cells constantly. This need to greatly expand the T cells leads to T cell exhaustion. 

Preventing Immunological Exhaustion

T cell exhaustion can have negative and long-lasting effects on a patient’s immune functionality. Exhaustion also greatly impacts the effectiveness of common adoptive T cell therapies, such as CAR T-cell therapy. These therapies rely on continuous cell supply, so gaining insight into preventing and reversing T-cell exhaustion could lead to more effective treatments and a better understanding of how to redirect the human immune response. 

Addressing Exhausted Expression Through Cell Activation

T cells that have been exhausted can have their effector functions reinvigorated through cell activation. The effector cells will regain their cytotoxic abilities by treating the exhausted cells with anti-inhibitory antibodies. 

Once T cells become exhausted, their genetic makeup is modified to express many inhibitory surface receptors that interfere with cytotoxic abilities. These receptors bind to ligands that effectively “turn off” the effector T cell or put it into an exhausted state of phenotypic expression. By blocking these receptors from binding to their ligands using targeted antibodies, T cell exhaustion can be reversed and the cells reactivated. 

Gentle Activation Reduces T Cell Exhaustion

Exhaustion results from constant interaction with an antigen, or continuous antigen stimulation. Activating T cells for cell therapy products presents a challenge to meet the demand for the number of T cells necessary for scalable clinical applications while balancing effectiveness . This intense and robust activation can cause increased T cell exhaustion, limiting the desired T cells’ therapeutic functionality. 

 Gentle activation methods are less prone to triggering T cell exhaustion due to the reduced amount of antigen escape, exposure, and overstimulation. Finding the appropriate balance between robust activation and limiting T cell exhaustion is critical to scalable cell therapies designed to eliminate tumors while protecting against autoimmunity. 

Akadeum’s Cell Activation Products Reduce T Cell Exhaustion

At Akadeum Life Sciences, we understand the need for reliable, scalable, and straightforward cell isolation and activation products. Our gentle buoyancy-activated cell sorting (BACS™) technology is specifically designed to handle large quantities of cellular material without damaging the desired cells. The most recent application of our innovative microbubble technology is our activation kits for ex vivo T cell activation. 

A December 2022 study shows the effectiveness of using microbubbles to aid in cell isolation, activation, and expansion, making Akadeum’s microbubbles a widely applicable tool for cell therapy production labs. Our microbubbles use buoyancy to activate cells while suspending in a solution, leading to robust proliferation and minimal exhaustion. The microbubbles’ buoyancy reduces the expanding cells’ antigen-exposure time by stabilizing it on the surface, limiting stimulation and exhaustion.