How Does The Immune System Work? Part 2: The Adaptive Immune System

Key Learning Objectives

• Learn about the adaptive immune system—the specific part of immunity
• Discover the cells of adaptive immunity and their functions
• Understand the importance of immunological tolerance and autoimmunity
• Find out what happens to adaptive immunity as we age

What Is the Adaptive Immune System?

The adaptive immune system is one of the two major divisions of the immune system, along with the innate immune system. As we learned in the first article of this miniseries, innate immunity is responsible for the first line of protection against pathogens. Physical and chemical barriers lining the outer surfaces and cavities of organs and blood vessels block the entry of pathogens into our body; when these are breached, innate immune cells (e.g., neutrophils, macrophages, dendritic cells, natural killer cells, basophils, eosinophils) devise quick responses in an attempt to neutralize pathogens^[1–3]. 

The responses of the innate immune system are non-specific in the sense that they distinguish different types of pathogens but they are not able to differentiate specific pathogens. In other words, they can distinguish a virus from a bacteria, but they can’t differentiate between two bacterial species. This is the most significant difference between the two types of immunity as adaptive immune responses are characterized by their specificity.

Adaptive immune responses are initiated by antigens (this is the name given to any molecule that can elicit an immune response) and mediated by a type of white blood cell called lymphocytes. At the surface of their cell membrane, lymphocytes express receptors that are able to detect antigens with a very high degree of specificity. Lymphocytes express a very diverse collection of these specific antigen receptors, meaning that they can recognize a very large number of antigens. 

Each group of lymphocytes with the same antigen receptor (i.e., the same specificity) is called a clone. The collection of all the different types of lymphocyte clones is called the lymphocyte repertoire. Having a larger lymphocyte repertoire means we have increased odds of recognizing and responding to pathogens. These antigen receptors form a kind of catalogue of possible threats to which they are ready to respond. It is estimated that lymphocyte receptors may detect up to 1 billion different antigens. The main advantages of this specificity are that it grants the ability to recognize new pathogens and create a memory of a specific infection, allowing the adaptive immune system to respond more effectively on subsequent exposures. But we’ll learn more about that further on.

Just like in innate immunity, the efficacy of adaptive immune responses depends on the ability of immune cells to communicate between themselves and with other cells of our body. It is this communication that allows them to activate each other, coordinate their actions, and devise an appropriate and effective immune response. These interactions are mediated primarily by a group of signaling proteins called cytokines. Cytokines are important molecules that participate in all aspects of immunity, from the activation, growth and differentiation of immune cells, to their migration and movement from the blood into tissues and within tissues. 

The adaptive immune system is responsible for a more complex and specific second wave of immune responses mediated by lymphocytes. It is a slower immune response that is acquired as the immune system faces challenges.

Cells of the Adaptive Immune System 

There are two major populations of lymphocytes called B cells and T cells, and they’re involved in different types of adaptive immunity, humoral and cell-mediated immunity, respectively. Each has its own set of mechanisms that allow them to devise optimized responses depending on the type of threat (e.g., extracellular vs intracellular pathogens, bacteria vs viruses)^[1–3].

Lymphocytes, like all blood cells, arise from stem cells in the bone marrow called hematopoietic stem cells (HSCs). B cells mature in the bone marrow, whereas T cells mature in the thymus. The bone marrow and the thymus are therefore known as the generative (or primary, or central) lymphoid organs. 

The mature lymphocytes that emerge from the bone marrow or thymus and that have never encountered a foreign antigen are called naïve lymphocytes. Naïve B and T cells can be thought of as being uncommitted: They are ready to be activated and programmed to fight off new, unrecognized infections and diseases. They are functionally quiescent (i.e., they’re in a resting state) and they circulate in the blood and in the lymphatic system. [Recall from part one that the lymphatic system drains extracellular fluid and immune cells from tissues and transports them as lymph. Lymph is filtered by small organs called lymph nodes, where immune cells are concentrated and sample the lymph looking for signs of infection. Lymph is eventually emptied back into the blood flow.] 

The adaptive immune response is initiated by the recognition of a foreign antigen. When they come across the antigen they recognize, the pre-existing antigen-specific clones are selected and activated, a process called clonal selection. As a result, lymphocytes specific for that antigen proliferate to generate thousands of progeny with the same specificity, a process called clonal expansion. 

As they proliferate, antigen-stimulated lymphocytes differentiate into effector cells, whose function is to eliminate the antigen, and into long-lived memory cells, which mediate faster and enhanced responses on subsequent encounters with the antigen.  

Adaptive immune response depends on naïve and memory cells. Naïve cells are activated when the antigen is something the immune system has not encountered before. Memory cells are activated when the antigen is something that has been encountered in the past and is remembered.

B Cells and Humoral Immunity 

Humoral immunity is the branch of adaptive immunity mediated by antibodies produced by B cells. It is mainly responsible for the defense against extracellular microbes and microbial toxins^[1–3]. 

Antibodies can be found bound to the surface of B cells, where they function as antigen receptors. Upon activation by a microbial antigen, naïve B cells proliferate and differentiate into antibody-secreting plasma B cells. Antibodies secreted into the blood and mucosal secretions neutralize microbes and microbial toxins by binding and coating them, thus blocking their interaction with host cells. Antibody-coated (opsonized) particles are also targeted for elimination by phagocytes. Phagocytes carry a type of receptors called Fc receptors, which recognize and bind antibodies that are attached to infected cells or invading pathogens, resulting in the stimulation of their phagocytic and microbicidal activities. 

Plasma B cells secrete different classes (called isotypes) of antibodies (also called immunoglobulins [Ig]): IgM, IgD, IgG, IgE, and IgA. These isotypes have different functions and are secreted in different circumstances and in response to different types of antigens. For example, IgM is the only isotype expressed by immature B cells, whereas IgD starts to be expressed when B cells exit the bone marrow to populate other tissues and is involved in their activation. In mature B cells, polysaccharides and lipids stimulate the secretion mainly of IgM antibodies, whereas protein antigens can induce the production of IgG, IgA, and IgE antibodies. IgG antibodies coat microbes and target them for phagocytosis by the neutrophils and macrophages of the innate immune system; both IgG and IgM activate the complement system that promotes phagocytosis and elimination of microbes. IgA is secreted from mucosal cells and neutralizes microbes in mucosal tissues, such as the respiratory and gastrointestinal tracts, thus preventing inhaled and ingested microbes from infecting the host. IgE is involved in immune reactions to parasites and in allergic reactions.

B cells produce antibodies, which either tag a microbe or an infected cell for attack by other parts of the immune system, or neutralize it directly. 

Figure 1: Activation of a naïve B cell.
Source: OpenStax, Microbiology; 18.4 B Lymphocytes and Humoral Immunity. License CC BY 4.0

T Cells and Cell-Mediated Immunity

Cell-mediated immunity is the branch of adaptive immune responses mediated by T cells. Its primary function is to destroy intracellular pathogens that are not accessible to antibodies by killing the cells they infected^[1–3]. 

T cells express a type of antigen receptor called αβ T cell receptor (TCR). TCRs can only recognize peptide antigens that are presented by a type of cell surface molecules called major histocompatibility complex (MHC). There are two classes of MHC molecules: class I MHC molecules can be expressed by any nucleated cell, whereas class II MHC molecules are preferentially expressed by specialized cells that can act as antigen-presenting cells (APCs). APCs include dendritic cells, macrophages, and B cells; a few other cell types, including endothelial cells and thymic epithelial cells, for example, can also express class II MHC molecules. Each class is recognized by different subsets of T cells and is associated with specific types of infections. 

Intracellular protein antigens (produced by intracellular microbes, viruses, or tumor development) generate peptides that are presented at the cell surface bound to class I MHC molecules. These are recognized by a type of T cells called CD8⁺ cytotoxic T lymphocytes (CTLs). All nucleated cells can signal that they’re infected or damaged by presenting class I MHC–associated antigens to CD8⁺ T cells. The main function of CD8⁺ CTLs is to kill those cells. CTLs carry cytotoxic granules which they release in the vicinity of infected cells when they are activated by an antigen. These granules contain the pore-forming cytolytic protein perforin, which facilitates the entry of other proteins into target cells, and proteolytic granzymes that trigger the death of target cells by apoptosis. 

While CD8⁺ cytotoxic T lymphocytes are part of adaptive immunity and natural killer (NK) cells are part of the innate immune system, both have a similar function: They target and destroy virally infected, senescent, and tumor cells.

Figure 2: Activation of a naïve CD8⁺ cytotoxic T cell (CTL).
Source: OpenStax, Microbiology; 18.3 T Lymphocytes and Cellular Immunity. License CC BY 4.0

Antigens from extracellular microbes, which do not express MHC molecules, can only be presented to T cells through intermediary cells; APCs are those intermediaries. APCs capture proteins from extracellular microbes, process them, and display peptide antigens in association with class II MHC molecules to be recognized by T cells. Class II MHC-bound antigens are preferentially recognized by a type of T lymphocyte called CD4⁺ helper T cells, which primarily activate effector mechanisms that eliminate extracellular antigens. CD4⁺ helper T cells stimulate the activity of innate immune system cells (e.g., macrophages, dendritic cells, NK cells, mast cells, eosinophils), and B cells and CTLs of the adaptive immune system via the release of cytokines. CD4⁺ cells also differentiate into another subset of cells called regulatory T cells (Treg) whose main function is to inhibit, and thereby control, immune responses.

Figure 2: Activation of a naïve CD4⁺ helper T cell by an APC.
Source: OpenStax, Microbiology; 18.3 T Lymphocytes and Cellular Immunity. License CC BY 4.0

T cells participate in cell-mediated immunity, responsible for the destruction of intracellular pathogens by killing the cells they infected.

Dendritic cells (DCs) are the most efficient APCs in activating naïve T cells. DCs express both class I and class II MHC molecules and present antigens to both CD8⁺ and CD4⁺ T cells. DCs capture antigens from their sites of entry or production and transport these antigens to secondary lymphoid organs (lymph nodes, spleen, and lymphoid tissue in epithelial barriers). Naïve T cells that circulate through these organs recognize the antigens, and primary immune responses are induced. Macrophages and B cells present antigens to helper T cells in the effector phase of cell-mediated immunity and in humoral immune responses, respectively. 

There are two additional types of T lymphocytes, γδ (gamma delta) T cells and natural killer T (NKT) cells (not to be confused with natural killer [NK] cells), that do not require MHC-associated antigen presentation. These cells produce cytokines and may contribute to host defense and inflammatory diseases. 

Immunological Memory

Lymphocytes survey our body continuously, looking for potential pathogens. When they come across an antigen they recognize, lymphocytes are activated, trigger a specific immune response, and proliferate, creating a pool of new lymphocytes with the same specificity^[1–3].

Some of these activated lymphocytes differentiate into memory cells and remain in our body after the threat is eliminated. They are called memory cells because they allow our immune system to “remember” previous infections and to devise a more effective response. Memory B and T cells persist and circulate in the human body in a functionally quiescent or slowly cycling state for months or years after the infection is eliminated. 

When they encounter the same antigen, their response is faster, greater, and more effective. Memory B cells will generate a quick and robust antibody-mediated immune response, whereas memory T cells will be quickly converted into large numbers of effector T cells upon reexposure to the specific antigen. Most likely, we won’t even know we were exposed to an infection. We will have become immune to that specific threat.

Memory B cells and T cells persist for months or years after the infection; they devise faster, greater, and more effective responses on subsequent exposures to the antigen that activated them.

Immunological Tolerance

As mentioned above, lymphocyte receptors are incredibly diverse, giving lymphocytes an extraordinary ability to recognize a vast collection of antigens, and consequently, a vast number of possible pathogens. However, it’s important to highlight that lymphocyte receptors do not exclusively recognize pathogens. The diversity of lymphocyte receptors is the result of random recombinations of antigen receptor gene segments. Therefore, the specificity of any lymphocyte receptor is also random^[1–3]. 

Lymphocytes recognize pathogens because of the extraordinary diversity of the lymphocyte repertoire: there are so many different receptors that it is highly unlikely that a microbial antigen will not activate a lymphocyte clone. But this also means that it is highly unlikely that there won’t be lymphocyte receptors that recognize our own normal molecules, i.e., self-antigens. Remember that an antigen is any molecule that may trigger an immune response, not necessarily a foreign molecule. But our lymphocytes don’t usually react to our molecules. Why? Because of immunological tolerance.

The immune system has the ability to distinguish between self and non-self antigens and to block responses to the molecules of our body through a set of complex mechanisms that allow tolerance to develop. For example, there are stages during lymphocyte maturation during which exposure to a self-antigen leads to cell death or replacement of a self-reactive receptor with one that is not self-reactive. The activity of regulatory T cells (Tregs) is also important, as they may block the activation of mature lymphocytes that recognize self-antigens, leading to their death by apoptosis.

Tolerance to self-antigens, also called self-tolerance, is a fundamental property of the normal immune system. Failure of self-tolerance results in immune reactions against self-antigens, known as autoimmunity. Self-tolerance is therefore extremely important for our health. 

Even when exposed to foreign antigens, there are circumstances in which lymphocytes do not mount an immune response. Depending on the conditions of exposure (e.g., persistence, location) and the presence or absence of other stimuli (e.g., regulatory T cells), foreign antigens may cause the inactivation and elimination of a lymphocyte clone, leading to tolerance to a specific microbe. This immunological tolerance to foreign antigens is what allows us to share our body with beneficial symbiotic microbes in the gut and the skin, for example. 

Immunological tolerance is the property of the immune system that stops it from reacting to the molecules of our body and to symbiotic microbes.

Immune-Privileged Tissues

There are tissues in our body that are immune-privileged, i.e., where immune responses and inflammation do not develop easily because they would carry a high risk of lethal organ dysfunction or reproductive failure. These include the brain, anterior chamber of the eye, testis, placenta, and fetus. Immune privilege in these tissues is possible due to a very effective isolation from the outside. Endothelial cells lining the blood vessels in these organs create a barrier that blocks the entry of pathogens, immune cells, and inflammatory mediators. They also produce local immunosuppressive cytokines and express cell surface molecules that inactivate or kill lymphocytes^[1–3]. 

Let’s take the brain as an example: inflammation in the brain can lead to the death of neurons, with very serious consequences. Therefore, the brain has characteristics that help block immune responses. For example, brain endothelial cells are very closely bound by tight junctions, which creates a barrier called the blood-brain barrier (BBB). The BBB is very effective at blocking the passage of immune cells and inflammatory mediators into the brain. In fact, the BBB is very effective at controlling the access of all types of substances to the brain. The brain also has its own type of resident macrophages, called microglia. Microglia are present in very high amounts throughout the central nervous system; they support neurons and they respond to tissue damage or infections in the brain. 

The trade-off of this immune privilege is that there are many other molecules that are also not able to get into and out of those tissues. This is why immune privilege is not a general property of our tissues. Most tissues need to be fairly permeable to macromolecules going in and out in order to sustain their functions.

Immune-privileged tissues limit immune responses because of a high risk of lethal dysfunction or reproductive failure. 

The Importance of a Healthy Adaptive Immune System

Aging has a significant impact on immunity, causing a set of changes, known as “immunosenescence,” that contribute to an increased susceptibility to infections. As we’ve seen in part one of this article series, age-related immune impairment is the result of a combination of changes in the cells, tissues, and circulating factors and signaling molecules of the immune system^[4,5]. 

Many aspects of adaptive immunity are considerably affected by aging, including the generation of new T cells and B cells from hematopoietic stem cells, the maintenance of the naïve lymphocyte pool, and the proliferation of effector cells. There is also an accumulation of atypical memory cells with a restricted antigen-receptor repertoire and less able to undergo clonal expansion and provide effective immunological defense. The responsiveness of B cells to new antigenic challenges (such as a vaccine) diminishes with aging and there is a decrease in the strength of antibody binding to antigens, which leads to a decrease in antibody-mediated protection. An increase in autoreactive immune cells is also observed. These changes decrease the ability to eliminate infections, impair the protection conferred by memory cells, and increase the likelihood of autoimmune reactions. 

Aging of the immune system is mainly driven by intrinsic factors, but just as any other aspect of the aging process, it can be accelerated or delayed by environmental and lifestyle factors. Supporting healthy metabolic pathways, for example, can have a positive impact on the immune system and contribute to healthy aging^[4,5].

References

[1] A.K. Abbas, A.H.H. Lichtman, S. Pillai, Cellular and Molecular Immunology E-Book, Elsevier Health Sciences, 2017.
[2] K.M. Murphy, C. Weaver, Janeway’s Immunobiology: Ninth International Student Edition, W.W. Norton & Company, 2016.
[3] J. Punt, S. Stranford, P. Jones, J. Owen, Kuby Immunology, Macmillan Learning, 2018.
[4] J. Nikolich-Žugich, Nat. Immunol. 19 (2018) 10–19.
[5] E. Montecino-Rodriguez, B. Berent-Maoz, K. Dorshkind, J. Clin. Invest. 123 (2013) 958–965.