The basis for most immune responses is the encounter between antigens and white blood cells. Microbes and other foreign substances enter most often through the respiratory or gastrointestinal mucosa and less frequently through other mucous mem branes or the skin. Antigens introduced intravenously become localized in the liver, spleen, bone marrow, kidney, and lung. If introduced by some other route, antigens are carried in lymphatic fluid and concentrated by the lymph nodes. The lymph nodes and spleen are important in concentrating antigens in areas where they will come in contact with antigen-presenting cells (APCs) and lymphocytes. APCs and lymphocytes can subsequently circulate into fluid compartments to seek out the antigens for which they are specific.
The Role of Antigen Processing and Presentation
In most immune reactions, the antigen is in a “raw” state and must be further acted upon by antigen-presenting cells (APCs) before it is ready for contact with T cells. Three different cells can serve as APCs: macrophages, dendritic cells, and B cells, although dendritic cells are the most common APC in the first contact with an antigen. Antigen- presenting cells modify the antigen so that it will be more immunogenic and recognizable. After processing is complete, the antigen is moved to the surface of the APC and bound to an MHC class II receptor to make it readily accessible to T cells during presentation (process figure 1).
Process Figure 1 Interactions between antigen presenting cells (APCs) and T helper (CD4) cells required for T-cell activation. (1) APCs (here a dendritic cell) are found in large numbers in lymphatic tissues, where they frequently encounter complex antigens such as microbes. APCs engulf the microbes, take them into intracellular vesicles, and degrade them into smaller, simpler peptides. (2) The antigen peptides are combined with MHC-II receptors and displayed on the surface of the APC. From its location on the cell membrane, the combination antigen/ MHC-II receptor is easily recognized by a T helper cell with a complementary receptor. (3) The MHC-II/antigen complex on the APC is recognized by two receptors on the T helper cell, the T-cell receptor and the CD4 coreceptor. Together, the two receptors recognize both the MHC receptor (self) and the antigen (nonself) simultaneously. Interaction between the CD80 molecule on the APC and CD28 molecule on the T helper cell is also needed for efficient activation of the T helper cell. (4) Physical binding, along with the release of Interleukin-12 by the APC, activate the T helper cell, stimulating it to release interleukins and assist other lymphocytes in their functions.
Before a T cell can respond to APC-bound antigens, certain conditions must be met. T-cell-dependent antigens, usually protein-based, require recognition steps between the APC, antigen, and lymphocytes. The first cells on the scene to assist in activating B cells and other T cells are a special class of T helper cells (TH). The T-cell receptor (TCR) of this class of T cell will bind simultaneously with the class II MHC receptor on the APC and with the antigen (process figure 1). A second interaction involves the binding of the T-cell CD4 receptor to the MHC of the APC. Finally, the CD80 protein on the APC binds to the CD28 protein on the T helper cell. Once this identification step has occurred, cytokines, primarily interleukin-1 (IL-1), produced by the APC, activate the T helper cell. The TH cell, in turn, produces a different cytokine, interleukin-2 (IL-2), which stimulates a general increase in activity of committed B and T cells. The manner in which B and T cells subsequently become activated by the APC–T helper cell complex and their individual responses to antigen are addressed below.
A few antigens can trigger a response from B lymphocytes without the cooperation of APCs or T helper cells. These T-cell– independent antigens are usually simple molecules such as carbo hydrates with many repeating and invariable determinant groups. Examples include lipopolysaccharide from the cell wall of Escherichia coli, polysaccharide from the capsule of Streptococcus pneumoniae, and molecules from rabies and Epstein-Barr virus. Because so few antigens are of this type, most B-cell reactions require assistance from T helper cells.
T-Cell Responses and Cell-Mediated Immunity (CMI)
The responses of T cells, referred to as cell-mediated immunities (CMIs), are among the most complex and diverse in the immune system. They involve several subsets of T cells that differ in their types of CD receptors and the precise ways they react against foreign antigens and cells (table 1). T cells are restricted, meaning that before they can be activated, they must have the antigen offered by an MHC complex on an APC (figure 1) to ensure recognition of self. All produce cytokines that, working together, carry out a spectrum of biological effects and immune functions. T cells differ notably from B cells in function. We will see that B cells combat foreign antigens by secreting molecules into the circulation, but in the case of T cells, the whole cell reacts directly in contact with target cells. T cells also stimulate other T cells, B cells, and phagocytes.
Table1. Characteristics of Subsets of T Cells
A T cell is initially sensitized by the binding of antigen/ MHC to its receptors, and the release of cytokines (principally interleukin-12) from the antigen-presenting cell. These events activate the T cell, preparing it for mitotic divisions, and causing it to form effector cells and memory cells that can interact with the anti gen if it is encountered. Memory T cells are some of the longest lived blood cells known (decades, rather than weeks or months for other lymphocytes).
The Activation of T Cells and Their Differentiation into Subsets
Mature T cells in lymphoid organs are primed to react with antigens that have been processed and presented to them by dendritic cells and macrophages. They recognize an antigen only when it is presented in association with a particular MHC carrier, but they differ in which carrier comes into play (process figure 2). T cells with CD4 receptors recognize endocytosed peptides presented on MHC II, and T cells with CD8 receptors (process figure 3) recognize peptides presented on MHC I.
Process Fig2. Activation and differentiation of T cell. (1) Antigen-presenting cells (APCs) present a combination of MHC II markers and antigenic peptides to T cells bearing CD4 markers. (2) The APC releases one or more cytokines (primarily interleukins). (3) Depending on the type of cytokine secreted by the APC, the CD4 cell will differentiate to become T helper 1 (TH1), T helper 2 (TH2), T helper 17 (TH17), T regulatory cells (Treg), or memory CD4 T cells. (4) TH1 cells, by secreting tumor necrosis factor (TNF) and interferon gamma (IF-γ), stimulate macrophages or TH2 cells. (5) TH2 cells stimulate the antibody-mediated immune response by activating B cells. (6) The secretion of still other combinations of interleukins and growth factors by the APC cause the CD4 cell to differentiate into TH17 cells, which increase inflammation, or T regulatory cells, which lessen the immune response.
Process Figure 3 Activation and differentiation of CD8 cells. (1) Antigen-presenting cells (APCs) present a combination of MHC I markers and antigenic peptides to T cells bearing CD8 markers. (2) TH1 cells secrete interleukin-2. (3) The CD8 cell differentiates into cytotoxic T cells (TC cells) and memory CD8 cells. (4) Cytotoxic T cells bind to self cells that have become cancerous or are virally infected, and they secrete proteins called perforins and granzymes. (5) Perforins and granzymes attack the target cell, eventually leading to its destruction.
T Helper (TH) Cells: Activators of Specific Immune Responses T helper (CD4) cells play a central role in regulating immune reactions to antigens, including those of B cells and other T cells. They are also involved in activating macrophages and increasing phagocytosis. They do this directly by receptor contact and indirectly by releasing cytokines such as interleukin-2, which stimulates the primary growth and activation of B and T cells, and interleukin-4, (along with several others) which stimulates the development of B cells. T helper cells are the most prevalent type of T cell in the blood and lymphoid organs, making up about 65% of this population. The severe depression of the CD4 class of T cells by HIV is a major factor in the immunopathology of AIDS.
When T helper cells are activated by antigen/MHC II, they differentiate into either T helper 1 (TH1) cells, or T helper 2 (TH2) cells, depending on what type of cytokines the antigen-presenting cells secrete. If the dendritic cell (APC) secretes IL-12, the T cell will differentiate to become a TH1 cell, which in turn will activate more T cells, promoting the cell-mediated immunity pathway. It is also involved in delayed hypersensitivity (process figure 15.10). Delayed hypersensitivity is a type of response to allergens, distinct from immediate allergies such as hay fever and anaphylaxis.
If the APC secretes another set of cytokines (IL-2, IL-4), the T cell will differentiate into a TH2 cell. These cells secrete substances that encourage B cell differentiation, promoting the antibody response.
Cytotoxic T (TC) Cells: Cells that Kill Other Cells When CD8 cells are activated by antigen/MHC I, they differentiate into T cytotoxic cells (TC or killer T cells). Cytotoxicity is the capacity of certain T cells to kill a specific target cell. It is a fascinating and powerful property that accounts for much of our immunity to foreign cells and cancer; and yet, under some circumstances, it can lead to disease. For a cytotoxic T cell to become activated, it must recognize a foreign peptide carried by an MHC-I receptor and mount a direct attack upon the target cell. The TC cell severely injures the target cell by secreting perforins1 and granzymes (process figure3). Perforins are proteins that can punch holes in the membranes of target cells, and granzymes are enzymes that digest proteins. First the perforins cause ions to leak out of target cells and create a passageway for granzymes to enter. Granzymes induce the loss of selective permeability followed by target cell death through a process called apoptosis. The apoptosis is genetically programmed and results in destruction of the nucleus and complete cell lysis and death.
Target cells that can be destroyed by TC cells include the following:
∙ Virally infected cells (process figure 3). Cytotoxic cells recognize and react against other cells that carry virus peptide MHC combinations expressed on their surface. Cytotoxic defenses are an essential protection against viral infections.
∙ Cancer cells. T cells constantly survey the tissues and immediately attack any abnormal cells they encounter (figure 4). The importance of this function is clearly demonstrated in the susceptibility of T-cell–deficient people to cancer.
∙ Cells from other animals and humans. Cytotoxic CMI is the most important factor in graft rejection. In this instance, the TC cells attack the foreign tissues that have been implanted into a recipient’s body.
Fig4. A cancer cell being attacked by two smaller cytotoxic T cells. The Tc cells release perforins and granzymes, which will perforate the membrane of the cancer cell. The cancer cell will soon collapse, while the T cells will remain alive and active. Steve Gschmeissner/Science Photo Library/Getty Images
T Regulatory (Treg) Cells: Modulators of Immune Function As we’ll explore further in chapter 16, an overactive immune system can be as bad as an underactive one. Regulatory T cells, or Tregs, express CD4 and CD25 receptors (see table 1) and prevent the immune system from overreacting. They play important roles in moderating inflammation, allergy, and autoimmunity, and in helping to ensure that the immune system doesn’t target the body’s normal microbiota.
Gamma-Delta T Cells: Specific and Nonspecific Activity Gamma-Delta T cells have attributes of both the nonspecific and specific immune responses. They bind to certain PAMPs on microorganisms in a manner similar to nonspecific WBCs like macro phages or dendritic cells. But they also display characteristics of a specific response, as the cells possess T-cell receptors which are re arranged to recognize a wide variety of antigens and produce memory cells when activated, acting like a “traditional” T cell. The biology of these cells is unclear for now, but they are known to be especially active against certain bacterial pathogens and tumor cells.
Natural Killer (NK): Defense against Cancer and Viral Infection Natural killer cells are a type of lymphocyte related to T cells. They circulate through the spleen, blood, and lungs, and are probably the first killer cells to attack cancer cells and virus-infected cells. They destroy these cells by mechanisms similar to those seen in cytotoxic T cells (figure 5). Because they lack antigen receptors, they are not specific for a single antigen, and so are not considered part of the specific, cell-mediated immune response.
Fig5. The action of natural killer (NK) cells. (a) (1) NK cell releases perforins, which polymerize and form a hole in the membrane of a foreign cell. (2) Granzymes from the NK cell enter the cell through the newly formed hole in the membrane. (3) The foreign cell dies by apoptosis. (4) Macrophage engulfs and digests the dead cell. (b) Scanning electron micrograph of a natural killer cell. (b): Science History Images/Alamy Stock Photo
Natural Killer T Cells (NKT Cells): A Hybrid of T Cells and NK Cells Natural killer T cells, a recently identified cell type, have properties of both T cells and NK cells. They express T-cell receptors and NK cell markers and are stimulated by both self and nonself lipids (recall that lipids are a primary component of cell mem branes). Once stimulated, they produce cytokines (like T cells) along with granzymes and perforins (like NK cells). Recent evidence shows an important role for these cells in the regulation of immune reactions against pathogens and tumors, as well as autoimmune and metabolic disorders.
T Cells and Superantigens Most of the T-cell responses we have covered so far are primarily beneficial and protective. But there is one type of reaction that often has drastic consequences and may lead to serious diseases. Such is the case in exposure of T cells to superantigens. These antigens, found primarily in bacteria and viruses, are actually a form of virulence factor. Examples include enterotoxin given off by pathogenic staphylococci, certain toxins of group A streptococci, and proteins of Epstein-Barr virus. They can provoke overwhelming immune responses by large numbers of T cells regard less of specificity. Superantigen molecules are structured so that they can span both MHC-II receptors and some antigen receptors (TCR) on T cells. This event can “trick” large numbers of T cells into releasing massive amounts of cytokines such as tumor necrosis factor and interleukins-1 and -6. The overwhelming influx of such potent mediators leads to blood vessel damage, toxic shock, and multiorgan failure. Multisystem inflammatory syndrome in children (MIS-C), a serious complication of COVID-19 in children, is thought to be the result of exposure to SARS-CoV-2 superantigens.
