The immune system is one of the most complex, nuanced biological systems that functions to keep the human race alive each and every day. It is both specific and broad, lifelong, and short-term, inherited and acquired, all at the same time. While it defends against deadly threats such as bacteria and viruses, defects in the immune system can be just as fatal. The Immune System 101 articles describe how this contradictory system works and will summarize the variety of functions of the immune system, its importance, and its potential failings in six different articles.
2. The Human Immune System 101: Adaptive Immunity
3. The Human Immune System 101: Bacterial & Viral Defenses Against the Immune System
4. The Human Immune System 101: The Overactive Immune System
5. The Human Immune System 101: The Underactive Immune System
6. The Human Immune System 101: The Immune System and Cancer
While the innate immune system relies upon the recognition of groups of molecules that are specific to pathogens, the adaptive immune system, which is typically recruited by the innate immune system, relies on the recognition of antigens (antibody generators) to stimulate cellular and humoral responses that are specific to each disease-causing organism and provide long term immunity. The cellular arm of adaptive immunity involves B cells and T cells, while the humoral arm utilizes antibodies (Alberts, Johnson, et al., 2002, Ch. 24). Each part of the adaptive immune system responds to one particular pathogen giving a person resistance to that particular disease-causing organism, but not to others. In this way, the adaptive immune systems display high degrees of specificity.
A person who recovers from measles, for example, is protected for life against measles by the adaptive immune system, although not against other common viruses, such as those that cause mumps or chickenpox. (Alberts, Johnson, et al., 2002, Ch. 24).
Figure 1: Innate vs. Adaptive Immunity. April Lowell. 2020.
Cellular Adaptive Immunity: B and T Cells
The cellular innate immune system involves a wide array of different cells; however, the cellular adaptive immune system is only compromised of two cell types—B and T cells. T cells are produced in the bone marrow, however, as their name suggests, mature in the thymus: a lymphatic gland located behind the sternum (Kumar, & Connors, 2018, p 1-3). These cells are essential for adaptive immune function; when they fail to function correctly, the results are typically disastrous and deadly, often resulting in opportunistic infections (Saharia, & Koup, 2013, p. 505). There are two major groups of T cells that will be focused on here: helper T cells and cytotoxic T cells.
To understand how helper T cells form, mature, and work, it is important to first understand the function of antigen-presenting cells (APCs). APCs “mature during the innate immune response” when an innate immune cell digests a pathogen and presents a portion of the pathogen—known as an antigen—on the surface of the cell membrane for recognition by adaptive immune cells (Hamilos, 1989, p. 98). Examples of APCs are dendritic cells or macrophages. A naïve T cell must receive two signals from the APC in order to mature into an effector cell—a cell that carries out an immune function. If the cell receives only one of the two signals, the T cell will undergo cell death instead of maturing into an effector helper T cell. The first signal comes from a foreign protein bound to a major histocompatibility complex (MHC) protein on the APC; “this peptide-MHC complex signals through the T cell receptor (TCR) and its associated proteins” (Alberts, Johnson, et al., 2002, Ch. 24). The second signal occurs when a group of B7 proteins, which are expressed on the APC membrane during the innate immune response, stimulate the CD28 receptor on the surface of a T cell. Once the signal is sent from the B7 protein, the effector T cell conversely promotes the expression of more B7 proteins “creating a positive feedback loop that amplifies the T cell response,” (Alberts, Johnson, et al., 2002, Ch. 24). The cell will become a helper T cell if it expresses a CD4 coreceptor on the cell surface that anchors the cell to the MHC receptors, while the T cell is classified as a cytotoxic T cell if it expressed the CD8 coreceptor (Andersen, & Schrama, 2006, p. 32-33).
Figure 2: Activation of a Helper T Cell by an APC. Wikimedia Foundation, Inc. 2022.
Helper T cells, or Th cells, assist in the activation of other immune cells such as B cells, innate immune cells, or cytotoxic T cells. One specific Th cell—Th1—“stimulates an inflammatory response by recruiting more phagocytic cells into the infected site,” (Alberts, Johnson, et al., 2002, Ch. 24). There are three principal ways in which this happens. First, Th1 cells can secrete pro-inflammatory cytokines that signal to the bone marrow to produce increased numbers of macrophages and neutrophils. Additionally, the cytokines released by these specific T cells cause macrophages and neutrophils to adhere to blood vessels. Finally, Th1 cells utilize specific cytokines that help direct innate immune cells to the site of infection (Alberts, Johnson, et al., 2002, Ch. 24). A second class of helper T cells—Th2—in conjunction with Th1 help to activate B cells. Once a helper T cell is activated by an APC through binding to a foreign protein bound to an MHC protein, it can then become an APC itself and “activate a B cell that specifically displays the same complex of foreign peptide and MHC protein on its surface,” (Alberts, Johnson, et al., 2002, Ch. 24). Quite literally, helper T cells do just that: they help to activate and recruit other parts of the immune system to rid the body of pathogens.
Figure 3: Activation of a B Cell by a Helper T Cell. Wikimedia Foundation, Inc. 2022.
While helper T cells are essential for activating a variety of different immune cells to launch a complete attack on foreign substances, cytotoxic T cells—also known as CD8 T cells—can cause infected cells, cancer cells, or bacteria cells to undergo cell death. The word cytotoxic means something that is toxic to cells, which is exactly the function of these particular immune cells. The activation of cytotoxic T cells is similar to that of Th cells involving a dual signal requirement and binding to MHC-antigen complexes on APCs; however, the mechanism of action differs between the two classes. Cytotoxic T cells work to kill target cells in three main ways. First, this specific class of T cell release cytokines such as tumor necrosis factor-alpha (TNF-α) and IFN-γ. TNF-α binds to receptors on the target cell, and triggers what is known as a caspase cascade; this cascade initiates apoptosis—or controlled cell death—thereby killing an infected cell or a cancer cell (Andersen, Schrama, et al., 2006, p. 37). The release of IFN-γ activates a different apoptotic pathway in target cells known as “Fas-mediated target-cell lysis,” (Andersen, Schrama, et al., 2006, p. 37). In another mechanism employed by cytotoxic T cells, one Fas receptor on the T cell surface binds to another Fas receptor on the target cell, thus triggering the caspase cascade and apoptosis. Furthermore, cytotoxic T cells can release cytotoxic proteins such as perforin and granzymes released from lysosomes in the T cell; once in the intracellular space, these proteins induce apoptosis that is once again dependent on the caspase cascade (Andersen, Schrama, et al., 2006, p. 37).
Figure 4: Cytotoxic T Cell Functions. Mads Hald Andersen, David Schrama, et al. 2006.
B cells are formed in the bone marrow, are essential for forming immunologic memory, and express diverse antibody—or immunoglobulin (Ig)—receptors on the cell surface that recognize a variety of different and specific antigens (LeBien & Tedder, 2008, p. 1570). This diversity is achieved through genetic recombination which allows the variable segment of the antibodies to be unique; “During the differentiation of the B Cells, a process of gene recombination is structured initially that codes for segments V (Variable), D (Diversity), and J (Joining) of the heavy chain (chain H) together with that of the genes for segments V and J of the light chain (chain L) of the membrane-bound immunoglobulin (mIg),” (Anaya, Cervera, et al., 2013, p. 77). This process gives Ig receptors their variations and allows B cells to recognize an array of antigens. Additionally, B cell receptors (BCRs), like TCRs, are an essential component for immune responses and consist of the membrane-bound Ig and a transmembrane portion that is responsible for intracellular signaling.
Figure 5: Antibody Structure. Douglas Fix. 2015.
Helper T cells and other APCs assist in activating B cells within germinal centers (GCs), which is “a specialized microenvironment of lymphoid tissue” where immune cells mature and proliferate (Anaya, Cervera, et al., 2013, p. 77). Once a B cell comes in contact with an APC or helper T cell that is presenting an antigen that is compatible with the BCR, the B cell undergoes a process in the GC known as isotype switching in which the antigen-binding site of the Ig remains constant, but the heavy and light chain regions change; this occurs after antigen recognition in order to change the function of the antibody as different antibody classes perform different functions, as will be discussed in the humoral adaptive immunity segment below (Hoffman, Lakkis, et al., 2015, p. 1-5). After isotype switching is completed, the B cell will differentiate into either a plasma cell or a memory B cell. Plasma cells circulate the blood and lymph system and release large amounts of antibodies with the same antigen-binding segment as the BCR that was activated in the GC (Hoffman, Lakkis, et al., 2015, p. 1-5). Memory B cells, once activated by antigens and differentiated, reside in tissues and secondary lymphoid organs, and circulate in the bloodstream for years to decades after exposure to an antigen. Upon secondary exposure to the same antigen that activated the cell in the first place, memory B cells can differentiate into plasma cells to destroy the threat and release antibodies for the humoral response. Memory B cells allow for long-term immunity as the pathogen is cleared much faster during secondary exposure than the first time (Seifert & Küppers, 2016, p. 2283-2286).
Humoral Adaptive Immunity
Antibodies secreted by B cells make up the whole humoral arm of the adaptive immune system. Circulating the blood and lymph systems independent of the cells that secrete them, the five different classes of antibodies perform various essential immune functions. IgM, IgD, IgG, IgA, and IgE antibodies are differentiated by their heavy chains which are constant and not involved in antigen binding (Hoffman, Lakkis, et al., 2015, p. 1-5). However, these regions do determine what function the antibody will carry out once it contacts its specific antigen. IgM and IgG3 function through activating the complement system to perforate and kill the target cells that the antibodies bind to. Whereas IgG1 and IgE recruit macrophages and other innate immune cells to destroy their targets. Other classes of antibodies, such as IgA and IgG4, may inactive viruses by simply binding to the virus, thereby preventing it from entering and infecting health cells binding (Hoffman, Lakkis, et al., 2015, p. 3).
Figure 6: The Five Classes of Antibodies. Lindsay M. Biga, Sierra Dawson, et al. 2020.
The adaptive immune system allows for specific and long-term immunity, utilizes antigen-presenting cells to activate T cells and B cells, and relies on free-floating antibodies to neutralize threats. While the innate immune system is broad and short-lived in its response, adaptive immunity can last for decades and is highly specific in what it targets; in spite of their differences these two branches work in tandem to launch a holistic immune response to protect their host from pathogens. The cellular and humoral arms of both innate and adaptive immunity are equally necessary to withstand the large array of disease-causing organisms that humans encounter daily.
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Cover Image: Kon, K. (2020). Antibodies Responding to an Infection of SARS-CoV-2. Getty Images Science Photo Library. [Illustration]. Image retrieved from https://arstechnica.com/science/2022/01/immune-system-vs-virus-why-omicron-had-experts-worried-form-the-start/ Figure 1: Lowell, A. (2020). Innate vs. Adaptive Immunity. Cell Signaling Technology, Inc. [Illustration]. Image retrieved from https://blog.cellsignal.com/immunology-overview-how-does-our-immune-system-protect-us Figure 2: Activation of a Helper T Cell by an APC. Wikimedia Foundation, Inc., Wikipedia®. (2022). [Illustration]. Image retrieved from https://en.wikipedia.org/wiki/T_helper_cell Figure 3: Activation of a B Cell by a Helper T Cell. Wikimedia Foundation, Inc., Wikipedia®. (2022). [Illustration]. Image retrieved from https://en.wikipedia.org/wiki/T_helper_cell Figure 4: Andersen, M. H., Schrama, D., Thor Straten, P., & Becker, J. C. (2006). CTL Mediated Cytotoxicity. [Illustration]. Image retrieved from https://www.jidonline.org/article/S0022-202X(15)32621-X/fulltext Figure 5: Fix, D. (2015). Antibody Structure. [Illustration]. Image Retrieved https://oncologypro.esmo.org/education-library/essentials-for-clinicians/lymphomas/immunoglobulins-and-b-cell-development Figure 6: Biga, L.M., Sierra D., Harwell, A., Hopkins, R., Kaufmann, J., LeMaster, M., Matern, P., Morrison-Graham, K. Quick, D., Runyeon, J. (2020). Five Classes of Antibodies. Oregon State University. [Illustration]. Image retrieved from https://open.oregonstate.education/aandp/chapter/21-4-the-adaptive-immune-response-b-lymphocytes-and-antibodies/