Adaptive Immunity

Characteristics of the Adaptive Immune Response

The adaptive immune system is an initially slow but highly specific source of immunity.¹ The adaptive immune system evolved later than–and from–the innate immune system in the course of evolution, is found only in jawed vertebrates, and is at its most sophisticated in humans.^2,7 The adaptive system theoretically has the ability to defend against virtually any pathogen.² Furthermore, the adaptive system has the ability to "remember" pathogens it has already been exposed to, which greatly speeds its reaction time to subsequent exposures, thereby providing lasting immunity, or "memory".

Cells of the Adaptive Immune Response

Dendritic cells. These starfish-shaped cells are the sentinels of the adaptive immune system. Dendritic cells are equipped with an array of different receptors, including pattern-recognition receptors like those found in the innate immune system. Found beneath epithelial cells throughout the body, and recently discovered in the brain, dendritic cells sample the extracellular fluid and become activated upon detection of molecular patterns characteristic of broad classes of microbial pathogens, or with exposure to certain cytokines. Thus, one characteristic that dendritic cells share with cells of the innate immune system is that they do not detect specific pathogens but rather characteristics common to many types of pathogens. However, they serve as an important bridge between the innate and adaptive immune systems. Activated dendritic cells carry samples of what they have taken in through the lymphatic system. Once the dendritic cell reaches the lymph node, it activates T-cells, thereby initiating the adaptive immune response.²

B-cells and the antibodies they produce. B-cells are produced in the bone marrow and then finish maturing in the spleen.⁸ B-cells produce specialized Y-shaped proteins called immunoglobulins (Igs). Igs serve as both cell surface receptors and secreted protein products called antibodies. Each cell's receptors and antibodies are capable of binding to a specific antigen, termed its "cognate antigen."^2,6 There are an estimated 100 million potential antigens, and a B-cell that is capable of targeting each of them is already present in the human immune system.² In order to accomplish this, B-cells have developed a process termed "somatic hypermutation" that allows B-cells to adapt their receptors to foreign antigens encountered. This provides a means to diversify a response at the level of an individual cell. Initially, only a few (~30) of each kind of B-cell are produced. Each B-cell is covered with thousands of receptors that target its specific antigen. If enough cognate antigen is encountered, it triggers a complex signaling pathway that ultimately leads to rapid cellular proliferation, such that about 20,000 clones of the cell can be made in just 1 week. These clones then quickly produce more copies of the B-cell receptor in the form of antibodies, which are secreted into the bloodstream.² Antibody production is fast and efficient: an activated B-cell can manufacture about 2000 antibodies per second!

When an antibody binds to its cognate antigen, the antigen is not destroyed, but opsonized to facilitate destruction by phagocytic cells. Furthermore, opsonization of a virus prevents it from infecting cells.

There are five subtypes of antibodies that have different structures and functions (IgM, IgG, IgA, IgE, IgD), and B-cells can shift their production from one type to another. Depending on the subtype, antibodies may help fight infection (IgG, IgM, IgA), facilitate activation of the complement cascade ("complement fixation"; performed by IgM and IgG antibodies), usher pathogens out of the intestinal and respiratory tracts (IgA), or stimulate mast cells and allergic responses (IgE). IgD immunoglobulins serve largely as B-cell receptors.^2,6,9

Activated plasma B-cells (the ones that produce antibodies) have a lifespan of only about 1 week²; however, a few mature B-cells become "memory cells" that are retained so that subsequent exposure to the same antigen allows for rapid activation and hence, relatively long-lasting immunity, for years in some cases.

T-cells. T-cells are similar to B-cells in that they have specific antigenic targets, proliferate in response to recognition of that antigen, and retain a few memory cells after an initial antigen exposure. The primary differences are that:²

• T-cells mature in the thymus.
• B-cells can recognize a variety of different types of molecules, but T-cells tend to recognize peptides generated from processed proteins.
• T-cell receptors generally recognize an individual epitope, but B-cell receptors can be multi-valent, recognizing 2 or more antigenic sites.
• T-cell receptors are found only on the surface of the T-cells, whereas B-cells can secrete those receptors in the form of antibodies.

There are several types of T-cells:

• CD4+ helper T-cells secrete cytokines that orchestrate the immune response and mobilize other cells to help eradicate a pathogen.^2,10 Helper T-cells also play a role in activating B-cells and selecting certain B-cells to become memory cells.^2,10
  
• CD4+ regulatory T-cells are less well understood than the other two types, but these cells help dampen the immune response to self-antigens and turn off the immune response once an infection has been cleared.² At least in part, regulatory T-cells do this by inhibiting the ability of CD4+ and CD8+ T-cells to respond to their cognate antigens, primarily through secretion of cytokines IL-10, IL-35, and transforming growth factor β.^{6, 11}
• CD8+ cytotoxic T-cells (also called killer T-cells) efficiently lyse cells that produce target antigens. Importantly, this gives them the ability to destroy virus-infected cells. Lysis is accomplished by production of perforin and granzymes. In addition, many cytotoxic T-cells express Fas ligand, which induces apoptosis when it binds with Fas on the surface of targeted cells.^2,6
• γδ T-cells: whereas most T-cells (≥95%) have receptors comprising α and β glycoprotein chains, a small minority (<5%) instead have γ and δ chains.¹² The role of these T-cells is still poorly understood, but there is some evidence that they may protect against skin cancer¹³ and may play a role in regulating the immune response.⁵ Some unusual features are:
  • Ability to bind to nonpeptide antigen that is not presented in MHC molecules
  • Expression of neither CD4 nor CD8
  • Migration of naive γδ T-cells into the tissues, particularly mucosal tissues, rather than circulation in the blood and lymph nodes.^5,14,15 Thus, in some respects, they act like cells of the innate immune system.

Generation of an Adaptive Immune Response

The adaptive immune system is a powerful weapon, and the body does not use it lightly. Cells in this system must all be activated before they can begin proliferating and carrying out their functions. For B-cells and T-cells, two steps are required for activation. This safeguard can be likened to the two keys needed to open safe deposit boxes, in which the box holder has a key unique to that box, and the bank teller has a key that fits all boxes, but both keys are needed to open any particular box.²

T-cell activation. In order for T-cells to become activated, their target antigen must be "presented" to them by another cell, and there must be a costimulatory signal. Costimulatory signals (which will be discussed in detail in Chapter 3) generally come from a second nonspecific activating ligand that fits the type of receptor found on the T-cell (eg, protein B7, which fits the CD28 receptor).^2,6

To present an antigen to T-cells, other cells display the antigen on their cell surface in MHC molecules. There are two types of MHC molecules:

• Class I MHC molecules are expressed in varying quantities on the surface of nearly all human cells. Fragments of internally synthesized proteins are fit into the specialized grooves of class I MHC molecules. Peptides displayed on class I molecules must be small (about 8—11 amino acids in length) to fit into the closed binding groove. The resulting peptide-MHC molecule complexes are then transported to the cell surface where they are displayed. These complexes serve as "billboards" to cytotoxic T-cells, letting them know what proteins are being manufactured inside the cell. Class I MHC molecule and peptide complexes are recognized by CD8+ cytotoxic T-cells because the CD8 coreceptor helps stabilize the T-cell's connection with these MHC-peptide complexes (Figure 1).^2,6
• Class II MHC molecules work similarly, but are displayed only by certain immune system cells, which are thus termed "antigen presenting cells." Class II MHC molecules have an open binding groove that can hold much larger peptides (13—25 amino acids in length) compared with class I MHCs. Antigen presenting cells include phagocytic cells, such as macrophages, and the proteins displayed are those that the antigen presenting cell phagocytosed from the extracellular environment. Class II MHC molecules and peptide complexes are recognized by CD4+ cells (helper and regulatory T-cells), with CD4 stabilizing the connection between the cells (Figure 1).^2,6

Figure 1. T-Cells Recognize Antigen-MHC Complexes.²

Class I MHCs, as a general rule, display fragments of peptides that are internally synthesized, which can include endogenous proteins, viral proteins in infected cells, and proteins overexpressed by oncogenes in tumor cells.^2,6 These fragments are inspected by cytotoxic T-cells. In contrast, class II MHC molecules display extracellular proteins that have been endocytosed. However, there are some rare but important exceptions called "cross-presentation." The most notable of these is that dendritic cells have been found to take up antigens produced by other cells and present them in association with class I MHCs to activate CD8+ cytotoxic T-cells.^16,17

Cells primarily accounting for presentation of class II MHC molecules to helper T-cells include B-cells, dendritic cells, and macrophages.^2,6 Dendritic cells are a special kind of antigen presenting cell in that, once activated, they have the ability to migrate to the lymph system, and specifically to the T-cell zone of lymph nodes.⁶ While traveling, dendritic cells upregulate expression of MHC class I and II molecules, increase production of B7 costimulatory proteins, and acquire the ability to produce cytokines (eg, IL-12, IL-23, IL-6), so that by the time a mature dendritic cell arrives at a lymph node it is primed to activate T-cells (Figure 2).^2,6 In contrast, activated macrophage cells tend to stay at the location of the infection and serve to restimulate arriving T-cells to maintain their activation if needed.² Activated B-cells are thought to play a role in later stages of infection, especially when much of a particular antigen has already been cleared.^2,6 Activated B-cells have the advantage of being able to concentrate larger quantities of antigen for presentation because B-cell receptors have high levels of affinity for their target antigen, acting almost like a magnet in collecting it. This antigen is then taken into the cell, processed, and transported back to the surface on class II MHC molecules.²

Figure 2. The Lifecycle of a Dendritic Cell.²

B-cell activation. B-cell activation can be either "cross-linkage dependent" or "T-cell dependent" (Figure 3).⁶ For cross-linkage–dependent activation, B-cells must bind to sufficient numbers of epitopes to bring B-cell receptors together on the cell surface ("cross-linking"), and the cell must receive costimulatory signals from cytokines. In general, a B-cell must bind to a considerable number of epitopes before it receives an activating signal; however, if its cognate antigen has been opsonized, the presence of complement fragments on its surface amplifies this signal, allowing for B-cell activation even when only a small amount of antigen is present.^2,6

For T-cell–dependent activation, B-cells connect with fewer epitopes but receive a costimulatory signal from helper T-cells. Although there may not be enough antigen for cross-linking to occur, B-cell receptors can still endocytose the antigen, degrade it into peptides, and display these peptides on class II MHC receptors where they will be detected by T-cells with receptors for that antigen. Once a T-cell recognizes the antigen-MHC complex, CD40L, present on the cell surface of an activated helper T-cell, binds with a CD40 receptor on the surface of a B-cell, sending an activating signal to the B-cell. At the same time, the T-cell releases cytokines that stimulate B-cell proliferation and growth.^2,6

Figure 3. B-Cell Activation Pathways.⁶

Long-Term Immunity

Upon a first exposure to a particular antigen, the innate immune system takes 1 to 2 weeks to mount a full immune response. Once activated, most cells in the innate immune system are short-lived. When activating signals are no longer received, the cells die. However, both B- and T-cells leave behind long-surviving "memory cells" that can reproduce and be activated much more quickly than naive B- and T-cells, if their cognate antigen reappears. In addition, some long-lived B-cells remain in the bone marrow and continue to produce antibodies that can provide lifelong immunity. Furthermore, memory B-cells remember which antibody type (IgG, IgA, IgE, IgM) to preferentially produce in response to that antigen. Thus, second exposures to an antigen prompt much quicker responses of greater magnitude and with higher-affinity antibodies.^2,6

Self-Tolerance

Since the adaptive immune system has the ability to recognize and destroy any antigen, the immune system must also have safeguards to protect the body's own normal healthy cells and proteins from destruction.

As T-cells mature in the thymus, they go through a two-part "screening test." The first screening selects only T-cells with the ability to recognize self-MHC, which is referred to as positive selection. Next, T-cells undergo negative selection to eliminate those that have a strong affinity for self-antigens on self-MHC. This screening process ensures that T-cells will recognize foreign antigen on self-MHC, but not unpresented antigen or self-antigen on self-MHC, or any antigen on foreign MHC. Only about 3% of all T-cells pass these screening tests and are allowed to mature and exit the thymus; the rest die via apoptosis. As another safeguard against recognition of self-antigens, mature but naive T-cells are allowed to circulate through secondary lymphoid organs, but generally cannot migrate out into the tissues where they might come into contact with rare self-antigens that were not tolerized in the thymus. Various other mechanisms serve as additional safeguards against T-cell activation by self-antigens, including suppression of activation by regulatory T-cells, the necessity of reasonably sustained contact between the T-cell and the antigen presenting cell for full T-cell activation, the need for costimulatory signals to fully activate T-cells (without which they become anergized), and additional tolerization performed by other cells outside the thymus or by continuous exposure to high levels of the antigen in lymphoid organs.^2,6,17-19

B-cells undergo a similar process of tolerization as they mature in the bone marrow. If a B-cell is produced whose receptors recognize a self-antigen, it is either eliminated or given a chance to "edit" its genes to produce a different, non–self-reactive receptor. Even with this opportunity for editing, only 10% of all B-cells ultimately pass the tolerance test and are released from the bone marrow. Like T-cells, naive B-cells are restricted to trafficking in the lymphoid organs, where they are unlikely to come into contact with rare self-antigens that were not tolerized in the bone marrow and are subject to other safeguards that help prevent autoimmunity.^2,6