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Tag words: immunity, pathogen, immunology, immune system, immunological system, immune response, adaptive immunity, acquired immunity, active immunity, passive immunity, antigen, antigen presentation, antibody, antibodies, lymphokine, complement, opsonization, antibody-mediated immunity, AMI, cell mediated immunity, CMI, IgG, IgA, IgM, IgE, B cells, T cells, NK cells, IL-1, IL-2, IL-4.









Kenneth Todar currently teaches Microbiology 100 at the University of Wisconsin-Madison.  His main teaching interest include general microbiology, bacterial diversity, microbial ecology and pathogenic bacteriology.

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Immune Defense against Bacterial Pathogens: Adaptive or Acquired Immunity (page 6)

(This chapter has 6 pages)

© Kenneth Todar, PhD

Cell-mediated Immunity
Cell-mediated Immunity (CMI )is a type of resistance in which cells of the immunological system are directly involved, but antibody production or activity is of minor importance. CMI differs from AMI in that immunity cannot be transferred (passively) from animal to animal by antibodies or serum, but can be transferred by lymphocytes removed from the blood.

The CMI response

During the cell-mediated immune response, various subsets of T lymphocytes are activated and develop into effector T cells. These include cytotoxic T lymphocytes (CTLs or Tc cells) and T helper cells of the TH1 and TH2 subsets. TH1 cells secrete lymphokines that activate macrophages and mediate delayed type hypersensitivity responses. TH2 cells secrete lymphokines that stimulate B cell development and may help activate Tc cells to their full cytotoxic capacity.

T cells that generate CMI are present in lymphoid organs, blood and lymph nodes. Due to constant recirculation between blood and lymph nodes via lymphatics and back to the blood, one T-cell circulates once in about 24 hours. Each carries receptors for the specific Ag with which it can react. T-cell recognition of Ag only occurs when the Ag is associated with proteins of the MHC complex. T-cells have receptors (TCR) complementary to the complexed MHC determinant and the antigenic epitope. TH1 cells and TH2 cells recognize Ag in association with MHC II (as displayed by macrophages and other APCs); Tc cells recognize Ag on cells complexed with MHC I (as displayed by altered self cells).

Stepwise Activation of Tc cells

During a primary CMI response, antigen is presented to the precursor Tc lymphocytes (CD8+) in association with MHC Class I proteins. All nucleated cells express MHC I on their surfaces, so virtually any cell in the animal expressing a new ("nonself") Ag on its surface will activate the cytotoxic T lymphocytes. TH2 cells can augment activation of Tc cells, but they probably are not required.

Activation of TH cells

TH-cells (CD4+) reacting with Ag may produce a variety of lymphokines. Notably, Interleukin-2 (IL-2) stimulates T-cell activation and IL-4 stimulates B cells.

T-helper cells are composed of distinct subsets that are best distinguished on the basis of their patterns of lymphokine production. Both types of TH cells develop under most conditions but their ratios and the predominance of certain lymphokines can vary, and this may mediate the pathology and outcome of certain bacterial infections.

TH1 cells "see" foreign Ag on the surface of APCs in the context of MHC II. Mainly, TH1 cells produce IL-2, gamma interferon (IFN) and lymphotoxin. This results in macrophage activation and the delayed-type hypersensitivity reaction, as well as help for Tc cell activation.

TH2 cells also see foreign Ag on the surface of APCs in the context of MHC II. Their response is to secrete IL-4, IL-5, IL-6, IL-10 and IL-13 that help activate B cells, provide help for the production of IgE that attaches to mast cells, and promote mast cell and eosinophil activation.

The lymphokines produced by TH cells stimulate B cells and pTc cells, inducing them to proliferate and mature into effector cells. Gamma Interferon activates macrophages and Natural Killer (NK) cells to their full cytolytic potential. Lymphotoxins, such as tumor necrosis factor (TNF) cause fever and kill cells at a distance.

Function of cytotoxic T-lymphocytes

Tc cells (CTLs) can destroy cells bearing new antigens on their surfaces (as might result in a viral infection, a tumor cell, or an infection by a bacterial intracellular parasite). Tc cells exert their cytotoxic activity when they are in physical contact with cells bearing new Ag in association with MHC I protein. Contact between the Tc cell and the target cell is required for lysis, although the exact mechanism of lysis is not well understood. The target cell membrane is damaged at the site of contact (the "kiss of death") leaving a gaping hole about 40 nm in diameter that cannot be repaired. When the Tc cell moves away 30-60 seconds later, there is leakage of the cell components, an influx of H2O, and the target cell swells up and dies. Apparently the Tc cell releases some of its cytolytic contents directly into the target cell, so that within a few minutes the target cell literally disintegrates. The Tc cell can move away and kill again.

Tc cells generally respond to Ag in association with MHC I proteins on the surface of a target cell. If they responded to Ag by itself, they could react with it when it was free in extracellular fluids, and their cytotoxic activity would be triggered with no purpose. As stated above, almost all host cells, including macrophages, display MHC I. Hence, an effector Tc cell can destroy a macrophage which is otherwise carrying out a useful function by presenting Ag to TH lymphocytes as part of the AMI or CMI responses. Usually, the time course of the response is such that TH cells have already developed and have carried out their (helping) function when Tc cells begin to become active.

Delayed Type Hypersensitivity

TH1-cells (CD4+) are a subset of T-lymphocytes that recognize Ag in association with Class II (and possibly Class I) MHC proteins. When TH1-cells are presented Ag in association with MHC II by a macrophage, their development is stimulated by macrophage Interleukin-1 (IL-1), and auto stimulated by IL-2, which the TH cell produces. They respond by differentiating and producing a variety lymphokines that induce a local inflammatory response, and which attract, trap, and activate phagocytes at the site. One aspect of this response is a state of delayed-type hypersensitivity in the host. This is usually evident in chronic infections wherein CMI is largely involved (e.g. tuberculosis).

Delayed-type hypersensitivity reactions usually present themselves as allergic reactions. Such allergic reactions generally require about 24 hours to develop following a secondary exposure to Ag. This time is required for the circulating TH cells (actually memory cells) to encounter the Ag and to produce cytokines that attract macrophages and Tc cells to the site wherein an allergic response is established. The phagocytic and cytolytic activities of these cells are responsible for the localized tissue destruction which occurs. Poison oak (ivy) rash is a familiar example of delayed hypersensitivity, but the reaction is also evident in several types of chronic or persistent bacterial infections including tuberculosis, leprosy and brucellosis, and in some fungal and protozoal infections.

One of the best known examples of the delayed-type hypersensitivity reaction is the Mantoux (tuberculin) test which is utilized to determine current or previous infection by the tubercle bacillus (Mycobacterium tuberculosis). A small amount of Ag called the purified protein derivative (PPD), derived from the cell wall of the bacterium, is injected subcutaneously under the skin of the forearm. The test is evaluated after 24-48 hours. A positive test is an allergic response (an "urticarial weal") at the site of the injection, which might look like a swollen reddened area about the size of a quarter. A negative test is no reaction. A positive test does not mean that the individual has an active case of tuberculosis, but that the individual has at least been exposed to the tubercle bacillus or one of its products sufficiently to have undergone a primary immune response. 

Other types of cells other than dermal macrophages have been proposed as antigen presenting cells (APCs) to initiate DTH reactions on the skin, including dendritic cells, epidermal Langerhans cells and venular endothelial cells. In humans, antigen presentation by Langerhans cells (which bear class II MHC), probably initiates sensitization, whereas antigen presentation by endothelial cells probably initiates DTH reactions upon secondary challenge.

5-hydroxytryptamine (5HT) has been shown to act as an adjuvant in the induction of the delayed-type hypersensitivity (DTH) response to purified protein derivative (PPD). This supports the hypothesis that DTH reactions mediated by macrophages and dendrocytes require a cascade of both inflammatory and immunological signals.

Involvement of macrophages in mediation of CMI

During induction of the cell-mediated immune response, macrophages play their usual role in the presentation of Ag to T helper cells and in producing cytokines that are involved in the initiation of immune reactions. In addition, as in the case of DTH (above), macrophages play a role in the expression of CMI. Many of the lymphokines produced by TH cells are aimed at attraction, entrapment and activation of macrophages at the site of the reaction. One of these lymphokines, Gamma Interferon, causes the local macrophage population to develop an increased number of lysosomes and increased ability to secrete microbicidal products. Oxygen-dependent killing mechanisms of the macrophage are stimulated, and the macrophage develops increased power to ingest and kill microorganisms. Such lymphokine-stimulated macrophages are referred to as "angry" or activated macrophages.

Compared to normal macrophages, activated macrophages exhibit much greater ability to destroy intracellular pathogens. Activated macrophages may play an important role in the recovery from chronic bacterial infections and in resistance to certain tumors. Activated macrophages may be able to overcome bacterial intracellular parasites which are able to thwart the macrophage killing mechanisms before activation.

Macrophage involvement in CMI may be part of the pathology of certain diseases. Where there is difficulty in elimination an intracellular parasite (e.g. the tuberculosis bacillus) the chronic CMI response to local antigens leads to the accumulations of densely-packed macrophages which release fibrinogenic factors and stimulate the formation of granulation and fibrosis. The resulting structure, called a granuloma, actually represents an attempt by the host to isolate a persistent infection.

Other Aspects of cell-mediated immunity

Another class of cytotoxic lymphocytes distinct from Tc cells may be stimulated during the cell-mediated immune response. These are referred to as Natural Killer or NK cells. NK cells are found in blood and lymphoid tissues, especially the spleen. They do not bear T cell (or B cell) markers. Like Tc cells, they are able to recognize and kill cells that are displaying a foreign Ag on their surfaces, but unlike Tc cells, they do not display TCR and they are not MHC-restricted.

NK cells are present in an animal in the absence of antigenic stimulation, and it is for this reason that they are referred to as "natural" killers. They might also be considered part of the innate immune defenses; however, NK cells become activated in a CMI response by T-cell lymphokines, including Interleukin-2 and gamma interferon.

Some NK cells are thought to be an immature form of a T-lymphocyte, but various other types of cells including macrophages, neutrophils and eosinophils, display NK activity. Some NK cells have surface receptors (CD16) for the Fc portion of IgG. They bind to target cells by receptors for the Fc portion of antibody that has reacted with antigen on the target cell. This type of CMI is called antibody-dependent cell-mediated cytotoxicity or ADCC. NK cells may also have receptors for the C3b component of complement, and therefore recognize cells that are coated with C3b as targets. ADCC is thought to be an important defense against a variety of parasitic infections caused by protozoa and helminths.

Summary: cells involved in expression of CMI

Cell mediated immunity (CMI) is carried out by several types of cells including macrophages, TH lymphocytes Tc lymphocytes, and NK cells. After an immunological encounter, these cells are activated to produce and/or respond to various classes of lymphokines that are the mediators of CMI. A summary of the role of these cells  in the expression of CMI is provided below.

Tc (cytotoxic) Lymphocytes (CTLs) kill cells bearing foreign Ag on surface in association with MHC I. Tc cells can kill cells that are harboring intracellular parasites (either bacteria or viruses) as long as the infected cell is displaying a microbial antigen on its surface. Tc cells kill tumor cells and account for rejection of transplanted cells. Tc cells recognize Ag-MHC I complexes on target cells, contact them, and release the contents of granules directly into the target cell membrane which lyses the cell.

TH Lymphocytes produce lymphokines that are "helper" factors for development of B-cells into antibody-secreting plasma cells. They also produce certain lymphokines which stimulate the differentiation of effector T lymphocytes and the activity of macrophages. TH1 cells recognize Ag on macrophages in association with MHC II and become activated (by IL-1) to produce lymphokines including gamma Interferon that activates macrophages and NK cells. These cells mediate various aspects of the CMI response including delayed type hypersensitivity reactions. TH2 cells recognize Ag in association with MHC II on an APC and then produce interleukins and other substances that stimulate specific B-cell and T-cell proliferation and activity.

Macrophages are an important as Ag-presenting cells (APCs) that initiate T-cell interactions, development and proliferation. Macrophages are also involved in expression of CMI since they become activated by gamma IFN produced in a CMI response. Activated macrophages have increased phagocytic potential and release soluble substances that cause inflammation and destroy many bacteria and other cells.

Natural killer (NK) cells are cytotoxic cells that lyse cells bearing new antigen regardless of their MHC type and even lyse some cells that bear no MHC proteins. Natural Killer cells are defined by their ability to kill cells displaying a foreign Ag (e.g. tumor cells) regardless of MHC type and regardless of previous sensitization (exposure) to the Ag. Some NK cells are probably derived from Tc cells (CTLs), but they do not display T cell markers. NK cells can be activated by IL-2 and gamma IFN. Natural Killers lyse cells in the same manner as CTLs. Some NK cells have receptors for the Fc domain of IgG and so are able to bind to the Fc portion of IgG antibody on the surface of a target cell and release cytolytic components that kill the target cell. This mechanism of killing is referred to as antibody-dependent cell-mediated cytotoxicity (ADCC).
 

Summary: Lymphokines involved in expression of CMI

Extracellular factors that affect cell proliferation and differentiation have been defined as cytokines. These include the lymphokines, which are proteins produced by T-lymphocytes that have effects on the differentiation, proliferation and activity of various cells involved in the expression of CMI. In general, lymphokines function by (1) focusing circulating leukocytes and lymphocytes into the site of immunological encounter; (2) stimulating the development and proliferation of B-cells and T-cells; (3) stimulating and preparing macrophages for their phagocytic tasks; (4) stimulating natural killer (NK) cells; (5) providing antiviral cover and activity. The names and functions of some of the important lymphokines are described below.

IL-1 (Interleukin-1): Initially called lymphocyte activation factor. Mainly a product of macrophages, IL-1 has a variety of effects on various types of cells. It acts as a growth regulator of T-cells and B-cells, and it induces other cells such as hepatocytes to produce proteins relevant to host defense. IL-1 forms a chemotactic gradient for neutrophils and serves as an endogenous pyrogen which produces fever. Thus, IL-1 plays an important role in both the immunological responses and in the inflammatory response.

IL-2 (Interleukin-2): stimulates the proliferation of T-cells and activates NK (natural killer) cells.

IL-3 (Interleukin-3): regulates the proliferation of stem cells and the differentiation of mast cells.

IL-4 (Interleukin-4): causes B cell proliferation and enhanced antibody synthesis.

IL-6 (Interleukin-6): (same as beta Interferon) has effects on B cell differentiation and on antibody production and on T cell activation, growth, and differentiation. Probably has a major role in the mediation of the inflammatory and immune responses initiated by infection or injury.

IL-8 (Interleukin-8): chemotactic attractant for neutrophils.

IL-13 (Interleukin-13): shares many of the properties of IL-4, and is a potent regulator of inflammatory and immune responses.

Interferons:  Gamma-Interferon (gamma IFN) is produced by T cells and may be considered a lymphokine. It is sometimes called "immune interferon" (alpha-Interferon is "leukocyte interferon"; beta-Interferon is "fibroblast interferon"). Gamma-interferon has several antiviral effects including inhibition of viral protein synthesis (translation) in infected cells. It also activates macrophages and NK cells, and stimulates IL-1, IL-2, and antibody production.

Lymphotoxins: (Tumor Necrosis Factor-Beta): (TNF-beta is produced by T cells; TNF-alpha is produced by T cells, as well as other types of cells.) TNF kills cells, including tumor cells (at a distance). It is also a pyrogen.

Colony Stimulating Factor (CSF): several, including GMCSF, cause phagocytic white cells of all types to differentiate and divide.
 

Contrasting Roles of the AMI and CMI Responses in Host Defense

AMI and CMI responses are generated during almost all infections, but the relative magnitude and importance of each type of response shows great variation in different hosts and with different infectious agents.

In some types of infections antibody plays a major role in immunity or recovery. For example, viruses producing systemic disease with a viremia stage (viruses free in the blood as they spread from infected to uninfected cells), such as poliomyelitis or yellow fever, can be neutralized by circulating antibody. Pathogenic bacteria that multiply outside of cells (nearly all bacteria) at sites accessible to antibody can  can be stopped by the forces of AMI. Diseases caused by circulating bacterial toxins (e.g. diphtheria and tetanus) are controlled by circulating antibodies that neutralize toxins. Circulating antibodies (and perhaps secretory IgA, as well) present in immune animals can prevent reinfection by pathogens.

In other types of infections CMI is of supreme importance in recovery. These tend to be infections where the microbe grows or multiplies intracellularly. Bacterial infections of this nature include tuberculosis, brucellosis and syphilis. Recovery is associated with development of a pronounced CMI response, even though it is CMI that contributes to the pathology of the disease.

The clearest picture of the importance of CMI in recovery from disease is seen in certain viral infections (e.g. herpes, pox viruses and measles). Viruses are always intracellular parasites and may only rarely expose themselves to the extracellular forces of AMI. Antibodies could neutralize free virus particles liberated from cells but often have little influence on infected cells. The best strategic defense against virus-infected cells seems to be to kill the infected cell when the virus may be in a replicative (noninfectious) form. Many viruses, as they mature, cause foreign (viral) antigens to appear on the infected cell surface. These cells are recognized by the host's CMI defenses and they become target cells for cytolysis. The infected cell can be destroyed before virus is liberated.

The CMI response also plays a role in destruction of tumor cells and in rejection of tissue transplants in animals. A major problem in transplantation of tissues from one individual to another is rejection which is often based on CMI response to "foreign" cells (not a perfect match antigenically). Since tumor cells contain specific antigens not seen on normal cells they also may be recognized as foreign and destroyed by the forces of CMI. If tumor cells develop on a regular basis in animals, it may be the forces o CMI that eliminate them or hold them in check The increase in the incidence of many types of cancer (tumors) in humans with advancement of age may be correlated with a decline in the peak efficiency of the immune system that begins about 25 years of age.

In summary, antibody-mediated immunity (AMI) is probably most useful as an immune defense because of its ability to neutralize or destroy extracellular pathogens and to prevent occurrence of reinfection. Cell-mediated immunity (CMI) plays the major role in immune defense against infections caused by intracellular parasites, infections caused by viruses (either virulent or oncogenic), rejection of transplanted tissues or cells, and in the destruction of tumor cells. The contrasting roles of AMI and CMI as specific immunological responses are presented in the following table.
 
 
Table 2. Relative Importance of AMI and CMI in Various Types of Infections
Type of Infectious Agent Immune Defense Mechanisms Examples
MULTIPLIES INSIDE TISSUE CELLS Prevent entry 

Kill infected cell

AMI: IgG, IgA, IgM 

CMI: Tc, NK, ADCC

viruses, Rickettsia
MULTIPLIES INSIDE PHAGOCYTES Activate phagocytes CMI: lymphokines viruses, Mycobacterium tuberculosis

Kill infected phagocytes CMI: Tc, NK, ADCC
MULTIPLIES OUTSIDE CELLS Kill microbe extracellularly AMI: Complement- mediated lysis most bacteria

Opsonized phagocytosis and lysis AMI: IgG, IgM

Neutralize toxins AMI: IgG, IgM
MULTIPLIES OUTSIDE CELLS BUT ATTACHMENT TO BODY SURFACES REQUIRED FOR INVASION Prevent attachment AMI: IgA streptococci E. coli Neisseria




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Kenneth Todar has taught microbiology to undergraduate students at The University of Texas, University of Alaska and University of Wisconsin since 1969.

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