If the immune "soldier" T cells do not get enough rest, the consequences are far more than just a "strike"!

As we age, the diversity of T cells decreases, and people tend to lose both naive and memory T cells, making them more susceptible to infection. The inability of T cells to remain in a quiescent state may be one reason they are more susceptible to infection and cancer.

T cells are an important part of the immune system and are the body's "soldiers" for defending against pathogenic microorganisms and fighting tumors. They remain in a resting state before detecting pathogens. Recently, a new study published in the journal Science pointed out that if T cells are not rested and maintained, they may die, making the host more susceptible to pathogen infection.

Graduate from the thymus "school" to become an immune "soldier"

The immune system includes central immune organs and peripheral immune organs. T cells are produced in central immune organs, mainly bone marrow and thymus. The English spelling of thymus is Thymus, which is why this group of cells is named T cells.

T cells migrate from bone marrow-derived lymphoid progenitor cells through the blood circulation to the thymus, where they undergo a series of complex development, differentiation, and screening processes and eventually mature. "It can be said that the thymus is the 'school' for training these 'soldiers'. T cells that 'graduate' from the thymus 'school' have not been exposed to real foreign antigen stimulation before entering the 'battlefield' and are in a resting state. They are called initial T cells or naive T cells," said Zhang Song, deputy director of the Institute of Immunology and professor of the School of Life Sciences at Nankai University.

After "graduation", T cells can circulate through the lymphatic and blood systems to peripheral lymphatic organs (such as the spleen, lymph nodes, tonsils, etc.) to play a role. Therefore, peripheral lymphatic organs are the battlefields for these "soldiers" to conduct actual combat. With the help of the lymphatic and blood circulation systems, T cells travel to immune organs and various tissues, just like patrolling "soldiers", monitoring foreign invaders in real time and maintaining the health of the body.

Most mature T cells express CD4 or CD8 receptor proteins on their cell surfaces, and therefore can be divided into two major T cell subsets: CD4+T cells and CD8+T cells. Once naive T cells discover and recognize foreign antigens during their patrol, they will activate, proliferate, and differentiate to perform their defense functions.

Initial T cells are activated by antigen stimulation. According to their active state, T cells can be divided into effector T cells and memory T cells. Memory T cells have long-lasting immune memory characteristics and maintain a resting state similar to initial T cells, so they can respond quickly and strongly when encountering the enemy again.

"According to the different functions they play, effector T cells can be divided into helper T cells, cytotoxic T cells and regulatory T cells." Zhang Song introduced these three types of effector T cells respectively. Helper T cells are involved in almost all adaptive immune responses. They not only help activate B cells to secrete antibodies and activate macrophages to eliminate ingested microorganisms, but also help activate cytotoxic T cells to kill infected target cells; cytotoxic T cells mainly identify virus-infected cells or cancer cells in the body, and induce apoptosis of diseased cells by secreting cytokines, which is an important line of defense for the body's antiviral and anti-tumor immunity; regulatory T cells are a type of T cell subpopulation in the immune system that has significant immunosuppressive and regulatory effects. Regulatory T cells can actively inhibit the overactivation of the immune system, which is crucial for maintaining immune homeostasis and preventing pathological self-reactions.

It takes three steps to kill the enemy in battle

"Raise your soldiers for a thousand days and use them in one moment." Initial T cells will circulate and reside between peripheral lymphoid tissues. When they encounter their specific antigens, that is, pathogenic microorganisms or viruses invading our bodies, the T cell "soldiers" will go into battle to kill the enemy. This process is called immune response, and the entire "combat" process requires "three steps."

"T cells cannot directly identify pathogenic microorganisms or viruses. The T cell-mediated immune response begins with the activation of naive T cells by antigen-presenting cells." Zhang Song introduced that antigen-presenting cells are activated by taking up antigens at the site of infection. The activated antigen-presenting cells migrate to the lymphoid tissues and process the taken-up antigens and display them on the cell surface to facilitate the recognition of naive T cells. Naive T cells recognize antigens by recognizing specific surface molecules of antigen-presenting cells, which is called the induction stage of the immune response.

While recognizing antigens, antigen-presenting cells further stimulate T cells through specific interactions between their surface molecules and T cell surface molecules, promoting T cell activation, proliferation and differentiation, which is called the reaction phase of the immune response.

After that, activated and differentiated T cells further perform effector functions by interacting with other cells or secreting cytokines, which is called the effector phase of the immune response. In the effector phase, differentiated helper T cells eliminate invading pathogens by secreting cytokines, promoting B cell activation and antibody secretion, and activating macrophages; while activated cytotoxic T cells directly induce apoptosis of infected cells by secreting cytokines such as granzymes and perforins.

During the immune response process, regulatory T cells can actively suppress the overactivation of the immune system to avoid damage to the body. "The information transmission and response effects between immune cells are both precise and powerful. T cells can kill infected targets with extremely high precision without affecting adjacent normal cells, minimizing damage to normal healthy tissues," said Zhang Song.

Part of the reason why T cells don't rest well has been discovered

In the absence of antigen exposure, T cells in peripheral lymphoid organs also need to rest and remain in a physiological resting state. This resting state is essential for fighting pathogenic microorganism infections and tumors, but its underlying molecular mechanisms remain largely unknown.

Recently, Science published online a major research result of Professor Chen Lieping's team at Yale University. The study found that in the absence of antigen exposure, self-activation of peripheral T cells from a resting state will lead to cell death, and the interaction between CD8α-PILRα molecules is crucial for maintaining the resting state of T cells.

"The CD8α molecule is a lineage marker of cytotoxic T cells and plays an important role in the development and antigen recognition of CD8+ T cells," Zhang Song explained.

In order to study the role of CD8α molecules in peripheral T cells, the research team constructed an inducible CD8α gene knockout system. This system can study the effects of CD8α on the functions of peripheral CD8+T cells while avoiding the effects on the development of CD8+T cells in the thymus.

Using this system, the research team found that genetic deletion of inducible CD8α disrupted the homeostasis of peripheral memory and naive CD8+ T cells, activated them from a quiescent state, and induced their programmed cell death, indicating that CD8α is essential for maintaining the quiescent state of peripheral CD8+ T cells.

In addition, the research team further used a genome-scale high-throughput screening system to identify the PILRα molecule as a ligand for CD8α. Blocking the interaction between CD8α-PILRα would lead to the disruption of CD8+T cell homeostasis and resting state.

Therefore, this study suggests that in the absence of antigen stimulation, the quiescent state of CD8+ T cells is maintained by a specific receptor-ligand (CD8α-PILRα) interaction on the cell surface, which may help to reduce the sensitivity of memory CD8+ T cells during antigen-induced activation, prevent them from being overactivated when not needed, and help them return to a normal state after the immune response subsides.

"This study provides a better understanding of the maintenance of naive and memory CD8+ T cells under normal and pathological conditions." Zhang Song introduced that a study published in Science magazine in 2020 showed that the VISTA protein on the surface of naive CD4+ T cells can regulate the resting state of CD4+ T cells.

In addition, T cells are artificially modified to target specific tumor antigens, which are called chimeric antigen receptor T cells (CAR-T cells). CAR-T cells have been increasingly used in tumor immunotherapy in recent years, but their anti-cancer activity is affected by cell exhaustion and loss of effector ability.

Zhang Song introduced that in 2021, another study published in Science magazine showed that inducing a short rest in CAR-T cells before cell exhaustion can cause them to switch from exhaustion to a memory-like state, thereby enhancing their anti-tumor ability.

As we age, the diversity of T cells decreases, and people tend to lose both naive and memory T cells, making them more susceptible to infection. The inability of T cells to remain in a quiescent state may be one reason they are more susceptible to infection and cancer.

In addition, the size of the thymus, the central immune organ of the human body, has obvious age characteristics. The thymus is relatively developed in infants and young children, reaches its peak development in adolescence, and then gradually degenerates and shrinks. It can be said that the thymus is an important place for the maturation of T cells. The degeneration of thymus function in the elderly will directly affect the production and function of T cells, leading to a decrease in the immunity of the elderly.