Source title: The consequences of insufficient rest of immune ‘soldiers’ T cells are far from “strikes”
The diversity of T cells decreases with age, and people tend to lose both naive and memory T cells, making older adults more susceptible to infection. The inability of T cells to remain quiescent may be one reason why they are more susceptible to infection and cancer.
T cells are an important part of the immune system and the “soldier” that the body uses to defend against pathogenic microorganisms and fight tumors. They remain quiescent until pathogens are detected. A new study published in the journal Science shows that if not rested and maintained, T cells can die, making the host more susceptible to pathogens.
Graduated from thymus ‘school’ to become immune ‘soldier’
The immune system includes central immune organs and peripheral immune organs. T cells are produced in central immune organs, mainly including bone marrow and thymus. The English spelling of the thymus is Thymus, which is why this group of cells is named T cells.
T cells migrate from bone marrow-derived lymphoid progenitor cells to the thymus through the blood circulation, where they undergo a series of complex development, differentiation and selection processes, and finally mature. “It can be said that the thymus is the ‘school’ for cultivating these ‘soldiers’. The T cells ‘graduated’ in the ‘school’ of the thymus have not been stimulated by real foreign antigens before entering the ‘battlefield’ and are at rest state, they are called naive T cells or naive T cells,” introduced Zhang Song, deputy director of the Institute of Immunology and professor of the School of Life Sciences, Nankai University.
The “graduated” T cells can circulate through the lymphatic and blood systems to peripheral lymphoid organs (such as spleen, lymph nodes, tonsils, etc.) to play a role. Therefore, the peripheral lymphoid organs are the actual combat positions of these “soldiers”. T cells travel through the immune organs and various tissues with the help of the lymphatic and blood circulatory systems, like patrolling “soldiers”, monitoring foreign invaders in real time and maintaining the body’s health.
Most mature T cells express CD4 or CD8 receptor proteins on the cell surface, so they can be divided into two major T cell subsets, CD4+ T cells and CD8+ T cells. Once the naive T cells discover and recognize foreign antigens during the patrol process, they will activate, proliferate, differentiate, and perform defense functions.
Naive T cells are activated by antigen stimulation. According to the active state, T cells can be divided into effector T cells and memory T cells. Memory T cells have long-term immune memory characteristics and maintain a resting state similar to that of initial T cells. Status, which can respond quickly and strongly when encountering an enemy again.
“According to the different functions, effector T cells can be divided into helper T cells, cytotoxic T cells and regulatory T cells.” Zhang Song introduced these three effector T cells respectively. Helper T cells are involved in nearly all adaptive immune responses, not only helping to activate B cells to secrete antibodies, activating macrophages to destroy ingested microorganisms, but also to help activate cytotoxic T cells to kill infected targets Cells; cytotoxic T cells mainly recognize virus-infected cells or cancer cells, and induce apoptosis of diseased cells by secreting cytokines, which is an important defense line of the body’s anti-virus and anti-tumor immunity; T-cell subsets with significant immunosuppressive and regulatory effects. Regulatory T cells can actively suppress the overactivation of the immune system and are essential for maintaining immune homeostasis and preventing pathological self-reactions.
Going into battle to kill the enemy requires “three steps”
“Raising a soldier for a thousand days is used for a while.” Primitive T cells circulate and reside among peripheral lymphoid tissues. When they encounter their specific antigens, that is, pathogenic microorganisms or viruses invade our body, T cells are “soldiers” It will go into battle to kill the enemy. This process is called immune response. The entire “battle” process requires “three steps”.
“T cells cannot directly recognize pathogenic microorganisms or viruses. The immune response mediated by T cells begins with the activation of naive T cells by antigen-presenting cells.” Zhang Song introduced that antigen-presenting cells are activated by ingesting antigens at the site of infection , the activated antigen-presenting cells will migrate to the lymphoid tissue, and at the same time process the ingested antigen and display it on the cell surface, which is convenient for the recognition of naive T cells. Naive T cells complete antigen recognition by recognizing antigen-presenting cell-specific surface molecules, which is called the induction phase of the immune response.
While recognizing the antigen, antigen-presenting cells will further stimulate T cells through the specific interaction of their surface molecules with T cell surface molecules, and promote the activation, proliferation and differentiation of T cells, which is called the response phase of the immune response.
After that, the 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 stage, 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 secrete granzymes and Cytokines such as perforin directly induce apoptosis in infected cells.
In the process of immune response, regulatory T cells can actively suppress the overactivation of the immune system to avoid damage to the body. “The messaging and response effects between immune cells are precise and powerful, and T cells are able to kill infected targets with extreme precision without affecting adjacent normal cells, minimizing damage to normal healthy tissue. ” Zhang Song said.
Part of why T cells don’t rest well, found
In the absence of antigen exposure, T cells in peripheral lymphoid organs also need to rest and will be in a physiological resting state. This resting state is crucial for fighting pathogenic microbial infections and tumors, but the underlying molecular mechanisms are very important. The extent is still unknown.
Recently, “Science” published online the major research results of Professor Chen Ping’s team at Yale University. The study found that in the absence of antigen exposure, the self-activation of peripheral T cells from the resting state will lead to cell death, and the CD8α-PILRα molecule The interaction of T cells is crucial for the maintenance of the quiescent 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.
To study the role of CD8α molecule in peripheral T cells, the research team constructed an inducible CD8α gene knockout system. This system avoids the impact on the development of CD8+ T cells in the thymus while realizing the functional effects of CD8α on peripheral CD8+ T cells.
Using this system, the research team found that gene deletion of inducible CD8α disrupts peripheral memory and homeostasis of naive CD8+ T cells, activates them from a resting state, and induces their programmed cell death, suggesting that CD8α is critical for maintaining peripheral The resting state of CD8+ T cells is critical.
In addition, the research team further utilized a genome-scale high-throughput screening system to identify the PILRα molecule as a ligand for CD8α, and blocking the interaction between CD8α-PILRα would lead to the disruption of CD8+ T cell homeostasis and resting state.
Thus, this study shows that in the absence of antigenic stimulation, the quiescent state of CD8+ T cells is maintained by a specific receptor-ligand (CD8α-PILRα) interaction on the cell surface, which may Helps desensitize memory CD8+ T cells during antigen-induced activation without overactivating them when they are not needed, and helps them revert to a normal state after the immune response has subsided.
“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 the journal Science in 2020 showed that the surface of naive CD4+ T cells The VISTA protein can regulate the resting state of CD4+ T cells.
In addition, T cells are engineered to target specific tumor antigens and are called chimeric antigen receptor T cells (CAR-T cells). CAR-T cells have been increasingly used in tumor immunotherapy in recent years, however, their anticancer activity is affected by cell exhaustion and loss of effector capacity.
Zhang Song introduced that in 2021, another study in the journal Science showed that inducing CAR-T cells to take a short rest before cell exhaustion can turn them from exhaustion to a memory-like state and enhance their anti-tumor ability.
The diversity of T cells decreases with age, and people tend to lose both naive and memory T cells, making older adults more susceptible to infection. The inability of T cells to remain quiescent may be one reason why 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 gland is relatively developed in infancy and young children, and develops at its peak during puberty, and then gradually degenerates and shrinks. It can be said that the thymus is an important place for the development and maturation of T cells, and the degeneration of the thymus function in the elderly will directly affect the production and function of T cells, resulting in a decrease in the immunity of the elderly.