The immune system serves as the body's defense line, capable of identifying and responding to invading pathogens to maintain the relative stability of the internal environment. This complex system consists of two main levels: innate immunity and adaptive immunity. Through the coordinated efforts of both, the body can effectively resist various external threats.

Innate immunity serves as the first line of defense in the immune system, relying on a series of physiological barriers such as the skin and mucous membranes, as well as the rapid initiation of inflammatory responses. This nonspecific immune response unfolds quickly upon pathogen invasion, providing preliminary protection against external threats. Meanwhile, adaptive immunity, as a further level of immune response, forms more specific immunological memory through the coordinated action of T lymphocytes and B lymphocytes (Su and Liu, 2021).

In this intricate immune network, immune memory cells have garnered widespread attention. Immunological memory refers to the long-term memory that the body develops and maintains for specific pathogens after the initial infection. The formation of this memory relies on two main types of cells: memory B cells and memory T cells. Upon the first infection, some B cells differentiate into memory B cells, which can survive for an extended period. Upon encountering the same antigen again, memory B cells can rapidly differentiate into antibody-producing cells, accelerating the clearance of the pathogen. Similarly, memory T cells also differentiate during the initial infection, possessing the characteristic of long-term persistence. When faced with the same antigen again, memory T cells can exert immune functions more rapidly and forcefully, forming a more enduring immune defense (Placek et al., 2019).

The immune system is not only a crucial defense line against infections but also a biological system with learning and memory functions. This memory function is manifested in the existence and activities of immune memory cells, allowing the immune system to recognize and respond to antigens more rapidly and accurately. This review will delve into the differentiation and functional mechanisms of immune memory cells, revealing their fine regulation and roles in the immune system. The aim is to provide a scientific basis for the precise regulation of immune memory, immunotherapy, and vaccine design.

1 Immune Memory Cell Classification

1.1 Memory B cells

Memory B cells are a special type of cell in the immune system that plays a crucial role in maintaining long-term immune memory. They enable the body to respond more rapidly and effectively to pathogens upon subsequent encounters. This holds significant importance in areas such as vaccine design, infection control, and immunotherapy.

The formation of memory B cells occurs during the initial infection when a portion of activated B cells differentiates into effector plasma cells, producing antibodies, while another portion forms memory B cells (Figure 1). These memory B cells have a long lifespan and can survive in the body for several years or even a lifetime, providing persistent immunity to previous infections. Memory B cells typically express specific cell surface markers, such as CD27. These markers help identify and distinguish the memory B cell population, allowing their specific location and function in the body to be determined (Nguyen-Contant et al., 2020).

Figure 1 B cell differentiation

The functionality of memory B cells in the immune system is primarily evident during secondary infections. When the same pathogen invades again, memory B cells can be rapidly and efficiently activated, subsequently differentiating into effector B cells that produce antibodies, thereby accelerating the clearance of the pathogen. This rapid response time is due to the memory established by memory B cells for specific antigens during the initial infection.

1.2 Memory T cells

Memory T cells are a specialized subset of T lymphocytes that play a crucial role in the immune system, responsible for maintaining memory of previous infections (Figure 2). The functionality of memory T cells in the immune system is primarily characterized by a rapid response to pathogens and the maintenance of long-term immune memory for prior infections. This ability is of significant importance in areas such as infection resistance, vaccine immunity, and immunotherapy. The immune memory network they establish in the body contributes to protecting the organism from infections and diseases.

Figure 2 Memory T cell

The formation of memory T cells involves the activation of T cells during the initial infection. Some of these activated T cells differentiate into effector T cells, participating in the direct attack against the pathogen. Another portion forms memory T cells, which have a longer lifespan and can persist in the body, providing immune memory to previous infections. Memory T cells typically express specific cell surface receptors and markers such as CD45RO, CD62L, etc. These markers aid in identifying and distinguishing the population of memory T cells, allowing their specific location and function in the body to be determined (Wang et al., 2023).

Memory T cells have a relatively long lifespan, with some capable of surviving for several years or even a lifetime. This long-lived characteristic enables them to maintain immune memory for specific antigens in the body. Upon re-exposure to the same pathogen, they can be quickly and effectively activated, accelerating the initiation of the immune response.

1.3 Other types of immune memory cells

In the immune system, besides memory B cells and memory T cells, there are also other types of immune memory cells. These cells, after a previous infection, can form immune memory and exhibit a faster and more effective response upon encountering the same or similar pathogens again. There are complex interactions among various cell types in the immune system. Memory B cells and T cells may collaborate with other immune cells, collectively building a comprehensive immune memory against pathogens. This interplay helps enhance the overall efficiency and flexibility of the immune system.

Natural Killer cells (NK cells) are a type of large granular lymphocyte that primarily participates in the killing of infected and tumor cells. Research indicates that NK cells can also form immune memory. Following a previous infection, activated NK cells may develop memory, allowing them to more quickly engage in killing activity upon encountering the same pathogen again. This type of memory helps enhance the immune system's long-term memory against specific pathogens (Hu and Zhu, 2023).

Macrophages are a type of phagocytic cell primarily responsible for clearing bacteria, dead cells, and other debris within the body. Research suggests that macrophages may also possess a certain degree of immune memory. During a previous infection, macrophages may acquire memory for specific antigens through the process of engulfing and processing pathogens, enhancing their response to subsequent infections.

Dendritic cells are a specialized type of antigen-presenting cell responsible for initiating and regulating immune responses. Research indicates that dendritic cells may also form immune memory. They assist in activating T cells by capturing, processing, and presenting antigens, thereby maintaining immune memory for pathogens following a previous infection.

Some other white blood cells, such as eosinophils and basophils, may also exhibit a certain degree of immune memory. These cells may acquire memory for specific antigens through different mechanisms following a previous infection, thereby enhancing the immune system's response to subsequent infections.

2 Functions of Immune Memory Cells

2.1 Secondary immune response

The secondary immune response refers to a faster and more potent reaction of the immune system when the host is re-exposed to the same or a similar pathogen after a previous infection by the same pathogen. This swifter and more effective response is primarily attributed to the presence of memory cells in the immune system, including memory B cells and memory T cells.

Secondary immune responses are faster compared to the immune responses during the initial infection. This is because after the initial infection, memory cells (memory B cells and memory T cells) have already formed and persisted in the immune system. Upon encountering the same pathogen again, these memory cells can be quickly activated, differentiating into effector cells, thus accelerating the clearance of the pathogen. The secondary immune response involves two main branches of the immune system, namely antibody-mediated immunity and cell-mediated immunity. Memory B cells can rapidly differentiate into effector B cells that produce antibodies, while memory T cells can enhance cellular immunity through direct action or by assisting other immune cells. This makes the immune response in the body more comprehensive and robust. The effectiveness of the secondary immune response is not only reflected in its rapid response but also in the persistence of immune memory. Memory cells can survive for a long time, some even throughout the lifetime. This enduring immune memory allows the body to respond quickly and effectively to the same pathogen in the future (Netea et al., 2019).

The design principles of vaccines are based on the concept of secondary immune responses. By introducing weakened or killed pathogens, parts of pathogen structures, or corresponding antigens into the host, vaccines activate the immune system to generate immune memory. When the host is re-exposed to the actual pathogen, the immune system can leverage the pre-formed immune memory to respond more quickly and effectively to the infection.

2.2 Role of immune memory cells in cancer immunotherapy

In cancer immunotherapy, immune memory cells play a crucial role. The primary goal of cancer immunotherapy is to stimulate the host's immune system to recognize, attack, and eliminate tumor cells (Figure 3).

Figure 3 Immunotherapy for cancer

Immune memory cells can survive and form long-term immune memory after prior exposure to antigens. In cancer immunotherapy, if patients have previously undergone immunotherapy or other immune-activating methods, memory B cells and memory T cells can be rapidly activated upon encountering the same antigen (tumor cell antigen) again, generating a quick and enduring immune response. An important strategy in cancer immunotherapy involves activating or enhancing the immune system's response to tumors through means such as vaccines, CAR-T cell therapy (Chimeric Antigen Receptor T-cell therapy), immune checkpoint inhibitors, etc. These treatment approaches can help establish anti-tumor immune memory, allowing the immune system to respond more effectively when encountering the same tumor antigen in the future (Zhao and Chen, 2020).

The presence of immune memory cells contributes to maintaining treatment effectiveness. In some immunotherapies, especially with the use of immune checkpoint inhibitors, patients may experience prolonged periods of stability or partial remission. This is associated with the existence and activity of immune memory cells, which play a crucial role in sustaining immune responses and controlling tumor growth. The presence of immune memory cells also provides an opportunity for personalized treatment. By gaining a deeper understanding of the patient's immune memory cell repertoire, doctors can better select appropriate immunotherapy strategies, thereby enhancing the level of individualization and efficacy in treatment.

2.3 Relationship between allergic reactions and immune memory cells

There is a close relationship between allergic reactions and immune memory cells. Allergic reactions are an exaggerated response of the immune system to substances (allergens) that are usually harmless to the body. This reaction involves various cells and molecules in the immune system, with immune memory cells playing a specific role in allergic reactions.

The occurrence of allergic reactions is related to the immune system developing allergic memory against antigens. Upon the initial exposure to an allergen, the body's immune system forms immune memory for that allergen, including memory B cells and memory T cells. These cells store information about the allergen, preparing for a more rapid and intense immune response upon future exposures. In allergic reactions, the heightened sensitivity of immune memory cells to specific allergens is a crucial factor. Allergens are typically common substances that should be harmless, but the immune system mistakenly identifies them as threats.

Allergic B cells and T cells in immune memory cells generate exaggerated and unconventional immune responses to allergens. Unlike conventional infections, the memory aspect of allergic reactions is more pronounced. Once the immune system forms immune memory for a particular allergen, upon subsequent exposure to that allergen, the immune system rapidly initiates an allergic reaction, leading to quick and intense symptom manifestation. The rapid and intense nature of this allergic reaction is closely associated with the presence and activity of immune memory cells.

In certain situations, the immune system's response to allergens may become excessively sensitive, leading to the occurrence of allergic reactions. This could involve abnormal activation or dysregulation of immune memory cells, causing them to trigger allergic reactions under circumstances where it wouldn't normally occur.

3 Regulation Mechanisms of Immune Memory Cells

3.1 Maintenance of immune memory

The maintenance of immune memory refers to the immune system's long-term retention of memory for antigens from previous infections or vaccinations. This ensures a quicker and more effective response upon re-encountering the same antigen. This process involves the coordinated action of multiple cell types and molecular mechanisms.

Immune memory cells have a relatively long lifespan. They can enter a dormant state, known as quiescence, to maintain prolonged survival. During the maintenance phase, when needed, these cells can be reactivated and enter a proliferative state to increase their numbers, enhancing the effectiveness of immune memory. The maintenance of immune memory cells is closely regulated by various cytokines. Cytokines are proteins produced by immune cells that play a role in signal transduction during immune responses. Interleukin-7 (IL-7) is a particularly important cytokine that can promote the survival and proliferation of immune memory cells (Liu et al., 2018).

The maintenance of immune memory involves long-term regulatory mechanisms. Specific gene expression, changes in chromatin structure, and the regulation of epigenetics play crucial roles in sustaining immune memory. These long-term regulatory mechanisms ensure that immune memory cells remain active for years or even a lifetime. When immune memory cells encounter the same antigen again, they are reactivated, rapidly proliferate, and differentiate into effector cells to respond to the infection. This reactivation process helps refresh the immune memory, maintaining an efficient response to the antigen.

External environmental factors can also influence the maintenance of immune memory. Factors such as chronic infections, inflammation, lifestyle, etc., may have an impact on immune memory. Therefore, maintaining immune memory depends not only on intracellular regulatory mechanisms but is also influenced by the external environment.

3.2 Genetic basis of immune memory

The genetic basis of immune memory refers to the genes and genetic mechanisms involved in the formation and maintenance of immune memory in the immune system. This includes genes that influence the formation, survival, and re-response to antigens of memory B cells and memory T cells.

The formation and maintenance of immune memory involve the regulation of gene expression. During the immune response, certain genes are activated or suppressed, leading to the differentiation, proliferation, and functional roles of immune cells. This regulation of gene expression involves multiple levels, including transcription factors, signaling pathway molecules, and more. The formation of immune memory begins with the recognition of antigens by immune cells. The genetic diversity encoding antigen receptors is a crucial genetic foundation for immune memory. In B cells, the immunoglobulin genes generate diverse antibodies through the combination of V (variable), D (diversity), and J (joining) genes. In T cells, the T cell receptors are formed through a similar mechanism. The major histocompatibility complex (MHC) genes play a crucial role in the formation of immune memory and antigen presentation. MHC molecules are responsible for presenting antigens to T cells, and an individual's MHC genotype determines how it recognizes specific antigens (Figure 4). Variations in MHC genotypes influence the sensitivity and specificity of the immune system to antigens (Christian, 2020).

Figure 4 Antigen presentation

Immune memory also involves the regulation of epigenetics, which means influencing gene expression through DNA methylation, histone modification, and other mechanisms without altering the DNA sequence. These epigenetic changes play a crucial role in the formation and maintenance of immune memory. Genetic polymorphism (i.e., differences in genotypes) between individuals plays a significant role in the diversity and variability of immune memory. The genotype of different individuals determines their sensitivity to antigens and their responses to immune challenges such as infections and vaccines.

3.3 Metabolic regulation of immune memory

The activity and function of immune memory cells are not only influenced by immune regulatory factors but also regulated by metabolic pathways. Metabolic regulation is a crucial aspect of the formation and maintenance of immune memory, affecting the generation, survival, and function of immune memory cells.

Generating and maintaining immune memory cells require a significant amount of energy. In terms of energy metabolism, immune memory cells tend to favor oxidative phosphorylation over glycolysis compared to other immune cells. This preference allows them to produce more ATP, providing the necessary energy for the maintenance of immune memory cells. Additionally, nutrient sensors such as AMPK (AMP-Activated protein kinase) and mTOR (Mammalian target of rapamycin) play a crucial role in regulating the metabolic balance of immune memory cells. By modulating the cellular energy state and metabolic pathways, these signaling pathways directly influence the generation and function of immune memory.

Lipid metabolism also plays a crucial role in the formation and maintenance of immune memory. By regulating the composition and properties of cell membranes, it influences signal transduction and membrane stability in immune memory cells. Additionally, immune memory cells can flexibly adjust their metabolic pathways to adapt to different environments. This adaptive adjustment enables them to survive and perform functions in nutrient rich or nutrient poor environments. A profound understanding of the metabolic regulation of immune memory cells contributes to the development of new therapeutic strategies to precisely control the formation and activity of immune memory, thereby better addressing infections, autoimmune diseases, and other immune-related disorders.

4 Summary and Outlook

Immune memory cells play an indispensable role in the immune system. The differentiation and functional mechanisms of memory B cells and memory T cells are crucial foundations for the formation of persistent immune memory against antigens. Memory B cells provide long-term antibody immunity by producing high-affinity antibodies, while memory T cells achieve persistent immunity against pathogens by regulating the activity of other immune cells. These cells collaborate within the immune system, offering a robust protective mechanism to ensure a quicker and more effective response to threats upon re-exposure to the same pathogens.

Gaining a deep understanding of the formation and function of immune memory cells is crucial for comprehending the fundamental principles of the body's immune system. Memory B cells, through their highly specific antibody production mechanism, provide the body with long-lasting and enduring immune defense. Similarly, memory T cells, by regulating other immune cells, further ensure the coordinated operation of the immune system. This establishment of long-term immune memory not only provides the body with persistent defense against infectious pathogens but also offers a profound theoretical foundation for vaccine design and immunotherapy.

In the future, the continuous advancement of technology can be leveraged to deepen the research on immune memory cells. The application of advanced single-cell technologies, high-throughput sequencing, and microscopy will contribute to a more comprehensive and in-depth understanding of the differentiation trajectories, epigenetics, and functional characteristics of immune memory cells. This will provide a more solid foundation for the development of precision medicine. However, practical clinical applications still face challenges, such as how to precisely regulate the activity of immune memory cells and how to address individual differences in different disease contexts. Future research needs to place more emphasis on integrating laboratory research with clinical practice to better promote the translational application of immune memory cell research (Jin et al., 2021).

In-depth research on immune memory cells has brought new insights to immunology, providing robust support for future medical research and clinical applications. Delving deeper into this field will help us better understand and fully utilize the functions of the immune system, offering humanity more efficient defense mechanisms.

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