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Chapter: Microbiology and Immunology: Structure and Function Imune System

Cells of the Lymphoreticular System

It is essential for the immune system to distinguish its own molecules, cells, and organs (self) from those of foreign origin (nonself).

Cells of the Lymphoreticular System

It is essential for the immune system to distinguish its own molecules, cells, and organs (self) from those of foreign origin (nonself). The innate immunity does this by express-ing germline-encoded pattern recognition receptors on the surface of its cells, receptors that recognize structures on potentially invasive microorganisms. The adaptive immunity, on the other hand, makes use of somatically gen-erated epitope-specific T-cell receptors (TCRs) and B-cell receptors (BCRs). These receptors are produced randomly and fresh within each individual T and B lymphocytes by gene

recombination prior to encounter with antigens (Fig. 16-2). The cells involved in the adaptive immune responses are (a) lymphocytes, (b) antigen-presenting cells (APCs), and (c) effector cells that function to eliminate antigens.


The lymphocytes occupy a very special place among the leukocytes.

·           They participate in immune reactions due to their ability to interact specifically with antigenic substances and to react to nonself antigenic determinants.

·           They also contribute to the memory of the immune system.

The lymphocytes consist of heterogeneous populations of cells that differ greatly from each other in terms of origin, lifespan, preferred areas of settlement within the lymphoid organs, surface structure, and function. They differentiate from stem cells in the fetal liver, bone marrow, and thy-mus into two main functional classes: B cells and T cells. They are found in the peripheral blood and in all lymphoid tissues.

The lymphocytes are classified depending upon where they undergo their development and proliferation: (a) T lympho-cytes or T cells undergoing development in the thymus or (b) B lymphocytes, or B cells undergoing development in the bone marrow. Differences between T cells and B cells are summarized in Table 16-1.

Thymus-derived cells

T lymphocytes, or T cells, are so designated because the thymus plays a key role in their differentiation. They are the key play-ers in adaptive immunity. They participate directly in immune responses as well as in orchestrating and regulating activities of other cells.

·           T cells constitute 65–80% of the circulating pool of small lymphocytes.

·           They are found in the inner subcortical regions but not in the germinal centers of the lymph nodes.

·           They have a longer life span (months or years) than B lymphocytes.

·           They are stimulated to divide on exposure to certain mito-gens, such as phytohemagglutinin or concavalin A, the T cells can be stimulated to divide.

·           Most human T cells have receptors for sheep erythrocytes on their surface and have the ability to form rosettes with them; this property is made use of for identifying T cells in a mixed population of cells.

The T lymphocytes perform two important groups of func-tions as follows:

Regulation of immune responses: Regulatory function ismediated primarily by helper (CD41) T cells, which produce interleukins.

Various effector functions: Effector functions are mediatedprimarily by cytotoxic (CD81) T cells, which kill allografts, tumor cells, and virus-infected cells. Depending on whether they have CD4 or CD8 proteins on their surface, T cells are subdivided into two major groups: CD41 T cells and CD81 T cells. Mature T cells have either CD4 or CD8 proteins, but never both.

CD41 T cells

CD4 cells are also known as helper T (Th) cells. They consti-tute about 65% of peripheral T cells and are found mainly in the thymic medulla, tonsils, and blood. CD4 displayed on the surfaces of these T cells recognize a nonpeptide-binding portion of MHC class II molecules. Hence, CD41 T cells are restricted to the recognition of pMHC class II complexes. Helper T lymphocytes are involved in the induction and reg-ulation of immune responses. CD41 T cells perform follow-ing helper functions:

·           They help B cells to be transformed into plasma cells.

·            They help CD81 T cells to become activated cytotoxic T cells.

·           They help macrophages to mediate delayed type hypersen-sitivity reactions.

All these functions are mediated by Th-1 cells and Th-2 cells— the two subpopulations of CD41 T cells:

·           The Th-1 cells activate cytotoxic T cells by producing IL-2.

·           They help in the development of hypersensitivity responses by producing primarily IL-2 and gamma interferon.

·           The Th-2 cells perform B-cell helper function by producing primarily IL-4 and IL-5.

The balance between Th-1 and Th-2 cells is regulated by gamma interferon and IL-12. Gamma interferon inhibits the production of Th-2 cells, whereas IL-12 increases the num-ber of Th-1 cells, thereby increasing host defense against microorganisms that are controlled by a delayed hypersensi-tivity reaction. Table 16-2 shows a comparison of Th-1 and Th-2 cells.

CD81 T cells

CD81 T cells are also known as cytotoxic T (Tc) and suppres-sor T (Ts) cells. They account for approximately one-third of all mature CD31 cells. They are found mainly in the human bone marrow and gut lymphoid tissue.

CD81 T glycoprotein displayed on the surfaces of these T cells recognize a nonpeptide-binding portion of MHC class I molecules. Hence, CD81 T cells are restricted to the recognition of pMHC class I complexes.

CD81 T cells perform mainly cytotoxic functions. They kill (a) virus-infected cells, (b) allograft cells, and (c) tumor cells. T-cell mediated cytotoxicity is an apoptotic process that appears to be mediated by two different pathways:

      (i)One pathway involves the release of proteins known as perforins, which insert themselves in the target cell membranes forming channels. These channels allow the diffusion of enzymes (granzymes, which are serine ester-ases) into the cytoplasm. The exact way in which gran-zymes induce apoptosis has not been established, but granzyme-induced apoptosis is Ca21-dependent.

 (ii) The other pathway depends on signals delivered by the cytotoxic cell to the target cell, which require cell-to-cell contact. This pathway is Ca21 independent.

The ratio of CD41 and CD81 T cells is approximately 2:1 in normal human peripheral blood. This may be significantly altered in immunodeficiency diseases, autoimmune diseases, and other disorders. Differences between CD4 and CD8 T cells are summarized in Table 16-3.

Activation of T cells

Recognition of complex on the surface of APCs, such as mac-rophages and dendritic cells, consisting of both the antigen and a class II MHC protein by TCR present on T cells, is most important for activation of helper T cells. Two signals are required to activate T cells:

·           The interaction of the antigen and the MHC protein with the T-cell-receptor-specific antigen is the first signal required in the activation of process. IL-1 secreted by the macrophages is also necessary for efficient helper T-cell activation.

·           A costimulatory signal is the second signal required for activation of T cells. In this signal, B7 protein present on the APC must interact with CD28 protein on the helper T cells. Following the costimulatory signal, IL-2 is produced by helper T cells, which is most crucial in producing a helper T cell capable of performing their regulatory, effector, and memory functions.

After activation of the T cells, a new different protein called CTLA-4 appears on the cell surface of T cells and binds to B7 by displacing CD28. The interaction of CTLA-4 with B7 inhibits T-cell activation by blocking IL-2 synthesis. This makes T cells to remain in a quiescent state and thereby plays an important role in T-cell homeostasis. On the other hand, mutant T cells that lack CTLA-4 and hence cannot be deactivated participate more frequently in autoimmune diseases.

Memory T cells

Memory T cells, as the name suggests, confer host immunity with the ability to respond rapidly and vigorously for many years after the initial exposure to a microbe or other foreign substances. The memory produced against a specific antigen shows the following characteristics:

1.        Memory cells live for many years or have the capacity to reproduce them.

2.        A large number of memory cells are produced, and so secondary response is enhanced and is greater than the primary response.

3.        Memory cells are activated by small quantity of antigens and require less costimulation than do the naïve and unac-tivated T cells.

4.        Activated memory cells produce greater amounts of interleukins than do naïve T cells when they are first activated.

T-cell receptor

T- cell receptor (TCR) for antigen consists of two polypep-tides: alpha and beta. These two peptides are associated with CD3 proteins. Each T cell has a unique TCR on its surface, thereby implying that hundreds of millions of different T cells occur in each person. Activated T cells as well as activated B cells produce large number of cells specific for those antigens. T-cell alpha and beta polypeptides show many similarities to immunoglobulin heavy chain in the following ways:

·           The genes coding for T-cell polypeptides are formed by rearrangement of multiple regions of DNA.

·           There are V (variable), D (diversity), J (joining), and C (con-stant) segments that rearrange to provide diversity, thereby resulting in more than 107 different receptor proteins.

·           RAG-1 and RAG-2 are the two genes that encode the recombinase enzymes that catalyze these gene rearrange-ments and are similar in T cells and B cells.

·           T cells, however, differ from immunoglobulins in the following ways:

·           T cells have two chains rather than four chains in immunoglobulins.

·           T cells recognize antigen only in conjunction with MHC proteins, whereas immunoglobulins recognize free antigens.

Effect of superantigens on T cells

Certain proteins such as staphylococcal enterotoxins and toxic shock syndrome toxins, and certain viral proteins, such as mouse mammary tumor virus, are called superantigens. These are called “super” because they activate a large number of helper T cells unlike “antigens”, which activate one or a few helper cells.

The superantigens play a very important role in patho-genesis of staphylococcal toxic shock syndrome caused by Staphylococcus aureus. In this condition, toxic shock syndrometoxin produced by S. aureus binds directly to class II MHC pro-teins without internal processing of the toxin. Subsequently, this toxin interacts with variable component of the beta chain (Vb) of the T-cell receptor of many T cells. The activation of T cells results in release of the interleukins, IL-2 from the T cells and tumor necrosis factor (TNF) from macrophages. These interleukins are responsible for many of the clinical presenta-tions observed in toxin-mediated staphylococcal diseases.

Effector functions of T cells

T cells perform two important functions: (a) cytotoxicity and (b) delayed hypersensitivity.

Cytotoxicity: Cytotoxicity activity of T cells is required primar-ily to destroy virus-infected cells and tumor cells. It also plays an important role in graft rejection. The cytotoxic T cells kill the virus-infected cells:

a)        By inserting perforins and granzymes (degrading enzymes) into the infected cell,

b)       By the Fas–Fas ligand (FasL) interaction, and

c)        By antibody-dependent cellular cytotoxicity (ADCC mechanism.


·    By inserting perforins and granzymes: Perforins are insertedinto the cells, leading to formation of a channel through the membrane. This results in the loss of cell contents and finally death of the cell. Granzymes are proteins that degrade proteins in the cell membrane, which also results in loss of cell contents. These enzymes also activate caspases that causes apoptosis, resulting in cell death.


·    By the Fas–Fas ligand (FasL) interaction: Cytotoxic T cellskill virus-infected cells by the FasL interaction. FasL is a pro-tein which is expressed on the surface of many cells. When a cytotoxic TCR recognizes an epitope on the surface of virus-infected cells, FasL appears on the cytotoxic T cells. When Fas and FasL interact, it results in death or apoptosis of target cells. NK cells can also kill target cells by FasL interaction.


·    By antibody-dependent cellular cytotoxicity (ADCC): Virus-infected cells can also be killed by ADCC. In this process, target cells are killed by a combination of IgG and phagocytic cells. The antibody bound to the surface of the infected cells is rec-ognized by IgG receptor on the surface of phagocytic cells (e.g., macrophages, NK cells) and the infected cell is killed. After killing of the virus-infected cells, the cytotoxic T cells are not damaged and can continue to kill other cells infected with the same virus. However, the cytotoxic T cells do not have any effect on free virus; they have effect only on virus-infected cells.


The cytotoxic T cells kill the tumor cells by a phenomenon called immune surveillance. New antigens are usually developed on surfaceof many tumor cells. These antigens bound to class I proteins are recognized by cytotoxic T cells, which are activated to proliferate by IL-2. The resultant clone of cytotoxic T cells can kill the tumor cells.

The cytotoxic T cells also play an important role in graft rejec-tion. In this process, cytotoxic CD8 cells recognize the class I MHC molecules on the surface of the foreign cells. Helper CD4 cells recognize the foreign class II molecules on certain cells, such macrophages and lymphocytes in the graft. The activated helper cells secrete IL-2, which stimulates the cytotoxic cells to produce a clone of cells, which kills the cells in the allograft.

Delayed hypersensitivity: The CD4 cells particularly the Th-1subset cells and macrophages mediate the delayed hypersensitiv-ity reactions against antigens of many intracellular pathogens. The CD4 cells produce interleukins, such as gamma interferon, macrophage activation factor, and macrophage inhibition fac-tor, which mediate delayed hypersensitivity reactions.

Th-1 cells produce IL-12-gamma interferon, which activates macrophages and thereby enhances the ability of the macro-phages to kill Mycobacterium tuberculosis. The gamma inter-feron, therefore, plays an important role in the ability of host immunity to control infections caused by M. tuberculosis, Listeriamonocytogenes, and other intracellular microbes. A deficiency ofCMI makes the person highly susceptible to infection by these microorganisms.

Regulatory functions of T cells

T cells play key role in regulating antibody production and in suppression of certain immune responses.

1.   Regulation of antibody production: Production of anti-bodies by B cells may be (a) T-cell dependent, requiring the participation of helper T cells (T-cell-dependent response), or (b) non-T-cell dependent (T-cell-independent response).

      In the T-cell-dependent response, all the classes of immuno-globulins, such as IgG, IgM, IgA, IgE, and IgD, are synthesized. The T-cell-dependent response produces memory B cells.

        In the non-T-cell dependent response (T-cell-independent response), only IgM antibody is synthesized. This response does not produce any memory cells. Hence, a secondary antibody response does not occur. In this response, the multivalent macromolecules, such as bacterial capsule polysaccharide are not effectively processed and presented by APCs; hence these do not activate helper T cells. This is because polysaccharides do not bind to class II MHC pro-teins, whereas peptide antigens do.

2.   Stimulation of helper and cytotoxic T cells to partici-pate in the CMI: In CMI, the antigen is processed by mac-rophages and is presented in conjunction with class II MHC molecules on the surface. These interact with the receptor on the helper T cells, which is then activated to produce IL-2, a T-cell growth factor that stimulates the specific helper and cytotoxic T cells to grow and participate in the CMI.

3.   Suppression of certain immune responses: T cells havebeen shown to inhibit several immune-mediated diseases in animals. Regulatory T cells (TR), also called suppressor T cells, is a subset of T cells and are associated with the suppression of certain immune responses. TR cells also called suppressor T cells are characterized by possessing CD25 marker and comprise 5–10% of the CD41 cells. The exact mechanism by which the regulatory cells suppress the immune response is not known. Imbalance in numbers or activity between CD4 and CD8 cells also leads to impair-ment of the cellular immune response of the host.

Bone marrow-derived cells

The bone marrow-derived lymphocytes are known as B lym-phocytes or B cells. Plasma cells are derived from mature B cells. Both B cells and plasma cells synthesize and secrete immunoglobulin.

B cells

B lymphocytes or B cells are so designated because the bursa of Fabricius, a lymphoid organ located close to the caudal end of the gut in birds, plays a key role in their differentiation. A mammalian equivalent of the bursa is yet to be found. Here the early stages of maturation of these lymphocytes occur in the bone marrow.

Origin of B cells: The clonal selection theory explains the ori-gin of antibody formation. According to this postulation, each immunologically competent B cell possesses receptor for either IgM or IgD that can combine with one antigen or closely related antigens. After binding of the antigen, the B cell is activated to proliferate and form a clone of cells. Selected B cells are trans-formed to plasma cells that secrete antibodies specific for the antigen. Plasma cells synthesize the immunoglobulin with the same antigenic specificity as those carried by activated B cells. The same clonal selection also occurs with T cells.

B cell precursors, during embryogenesis, first proliferate and develop in the fetal liver. From there, they migrate to the bone marrow, the main site of B-cell maturation in the adults. Unlike T cells, they do not require the thymus for maturation. The Pre-B cells have only m heavy chains in the cytoplasm but do not have surface immunoglobulins and light chains. Pre-B cells are found in the bone marrow, while B cells are found in the circulation. B cells mature in two phases:

·           Antigen-independent phase, which consists of stem cells and pre-B cells

·           Antigen-dependent phase, which consists of the cells, such as activated B cells and plasma cells that proliferate on inter-actions of antigen with B cells.

B cells possess surface IgM, which acts as a receptor for antigen. Some B cells may also carry on their surface IgD as receptor for the antigen. There are many other molecules expressed on the surface of the B cells, which serve different functions. A few of them are B220, class II MHC molecules, CR1 and CR2, CD40, etc.

Activation of B cells: Activation of B cells to produce the fullrange of antibodies first requires recognition of the epitope by the T-cell-antigen receptor and the production of IL-4 and IL-5 by the helper T cells. In addition, it also requires other costimu-latory interactions of CD28 on the T cells with B7 on the B cells. The CD28–B7 interaction is essential to produce IL-2. It also includes CD40L on the T cells, which must interact with CD40 on the B cells. The CD40L–CD40 interaction is essential for class switching from IgM to IgG and for switching between other immunoglobulin classes to take place.

Effector functions of B cells: Production of many plasmacells is the end result of activation of B cells. The plasma cells in turn produce large amounts of immunoglobulins specific for the epitope of the antigen. Some activated B cells also produce memory cells, which remain in a stage of quiescence for months or years. Most memory B cells have surface IgG that acts as the antigen receptor, but some even have surface IgM. These quiescent memory cells are activated rapidly on reexposure to antigen. Memory T cells produce interleukins that facilitate antibody production by the memory B cells. The presence of these cells is responsible for the rapid appearance of antibody in the secondary immune responses.

Antigen-presenting cells

Antigen presenting cells (APCs) include (a) macrophages and (b) dendritic cells.


The mononuclear phagocytic system consists of monocytes circulating in the blood and macrophages in the tissues. The monocyte is considered a leukocyte in transit through the blood, which becomes a macrophage when fixed in a tissue. Monocytes and macrophages as well as granulocytes are able to ingest par-ticulate matter (microorganisms, cells, inert particles) and for this reason are said to have phagocytic functions. The phago-cytic activity is greater in macrophages, particularly after activa-tion by soluble mediators released during immune responses, than in monocytes. Differentiation of a monocyte into a tissue macrophage involves a number of changes as follows:

a)        The cell enlarges 5–10 folds.

b)         Its intracellular organelles increase in number and complexity.

c)        It acquires increased phagocytic ability.

d)       It produces higher levels of hydrolytic enzymes.

e)        It begins to secrete a variety of soluble factors.

Macrophage-like cells serve different functions in different tissues and are named according to their tissue location. Examples include (a) alveolar macrophages in the lung, (b) histiocytes in connective tissues, (c) Kupffer cells in the liver, (d) mesangial cells in the kidney, (e) microglial cells in the brain, and (f) osteoclasts in the bone.

        For their participation in the immune reaction, the macro-phages need to be stimulated and reach an “activated state.”

·           Macrophages can be activated by various cytokines, compo-nents of the bacterial cell wall, and mediators of the inflam-matory response.

·           Gamma interferon produced by helper T cells is a potent activator of macrophages and is secreted by various cells in response to appropriate stimuli. Bacterial lipopolysaccha-rides (endotoxin), bacterial peptidoglycan, and bacterial DNA are the substances that also activate macrophages.

·           Activated macrophages are more potent than normal macro-phages in many ways, such as having greater phagocytic abil-ity and increased ability to kill ingested microbes. They are better APCs, and they activate T-cell response in a more effec-tive manner. By secreting various cytotoxic proteins, they help in eliminating a broad range of pathogens, including virus-infected cells, tumor cells, and intracellular bacteria.

Functions of macrophages: Macrophages perform threemain functions: (a) phagocytosis, (b) antigen presentation, and (c) cytokine production (Table 16-4).

       Phagocytosis: Phagocytosis of bacteria, viruses, and other for-eign particles is the most important function of macrophages. The macrophages on their cell surfaces have Fc receptors that interact with Fc component of the IgG, thereby facilitating ingestion of the opsonized organisms. They also have recep-tors for C3b, another important opsonin. After ingestion, the phagosome containing the microbe fuses with a lysosome. The microbe within the phagolysosome is killed by reactive oxygen, reactive nitrogen compounds, and lysosomal enzymes.


         Antigen presentation: After ingestion and degradation offoreign materials, the fragments of antigen are presented on the macrophage cell surface in conjunction with class II MHC proteins for interaction with the TCR of CD41 helper T cells. Degradation of the foreign protein is stopped following the association of antigen with the class II MHC proteins in the cytoplasm. This is followed by transportation of the complex to the cell surface by transporter proteins.


       Cytokine production: Macrophages produce several cytokinesincluding the IL-1, TNF, and IL-8. IL-1 plays an important role in activation of helper T cells, while TNF plays as important mediator in inflammatory reactions. IL-8 attracts neutrophils and T cells to the site of infection.


Dendritic cells

Dendritic cells are so named because of their many long, nar-row processes that resemble neuronal dendrites, which make them very efficient at making contacts with foreign materials. They are primarily present in the skin (e.g., Langerhans cells) and the mucosa, from where they migrate

Four types of dendritic cells are known: (i) Langerhans cells, (ii) interstitial dendritic cells, (iii) myeloid cells, and (iv) lymphoid dendritic cells. All these cells constitutively express high levels of  both class II MHC molecules and members of the costimulatory B7 family. Following microbial invasion or during inflamma-tion, mature and immature forms of Langerhans cells and inter-stitial dendritic cells migrate into draining lymph nodes, where they make the critical presentation of antigen to TH cells, which is required for the initiation of responses by those key cells.

Follicular dendritic cells

Follicular dendritic cells are similar to the dendritic cells except for their sites of presence and functions. These cells are pres-ent in B-cell-containing germinal centers of the follicles in the spleen and lymph nodes. These cells do not present antigen to helper T cells, but combine with antigen–antibody complexes by Fc receptors found on their surfaces.

Effector cells that function to eliminate antigens

Plasma cells

Plasma cells originate from terminally differentiated B cells. Plasma cells are oval or egg-shaped structures characterized by a stellate (star-like pattern) nucleus, nonstaining Golgi, and basophilic cytoplasm.

·           The main function of the plasma cells is to produce and secrete all the classes of immunoglobulins into the fluids around the cells.

·           They secrete thousands of antibody molecules per second, which are specific for the epitope of the antigen for a few days and then die.

·           They, however, do not express membrane immunoglobulins.

·           They divide very poorly, if at all, and are usually found in the bone marrow and in the perimucosal lymphoid tissues.

·           They have a short lifespan of 30 days during which they produce large quantities of immunoglobulins.

Natural killer cells

Natural killer (NK) cells are morphologically described as large granular lymphocytes. These cells are called natural killer cells due to their ability to kill certain virally infected cells and tumor cells without prior sensitization. Their activities are not enhanced by exposure and are not specific for any virus. NK cells comprise approximately 5–10% of peripheral lymphocytes and are found in spleen and peripheral blood.


NK cells develop within the bone marrow and lack TCR, but possess another set of receptors called killer activation recep-tors and killer inhibition receptors. They also posses NK T cells, another subset of T cells, which share some functional char-acteristics with NK cells. These NK T cells unlike NK cells are stimulated by lipids, glycolipids, and hydrophobic peptides presented by a nonclassical class I molecule CD1D and secrete large amounts of cytokines, especially IL-4.

The main functions of the NK cells are to kill virus-infected cells and tumors. They do so by secreting cytotoxins, such as perforins and granzymes similar to those of cytotoxic T lym-phocytes and also by FasL-mediated apoptosis. They kill the viruses without presence of specific antibodies but by a mech-anism called ADCC. Both IL-12 and gamma interferons are potent activators of NK cells.


Granulocytes are a collection of white blood cells with seg-mented or lobulated nuclei and granules in their cytoplasm, which are visible with special stains. The granulocytes are classified as neutrophils, eosinophils, or basophils on the basis of cellular morphology and cytoplasmic-staining characteristics.

Both neutrophils and eosinophils are phagocytic, whereas basophils are not. Eosinophils play an important role in defense against parasitic infections, though their phagocytic role is significantly lower than neutrophils. Basophils, on the other hand, are nonphagocytic granulocytes that function by releasing pharmacologically active substances from their cyto-plasmic granules. These substances play a major role in certain allergic responses.

Mast cells are the other granulocytic cells that have a role in the immune system. These cells are found in a wide variety of tissues, including the skin, connective tissues of various organs, and mucosal epithelial tissue of the respiratory, genitourinary, and digestive tracts. Like circulating basophils, these cells have large numbers of cytoplasmic granules that contain histamine and other pharmacologically active substances. Mast cells, together with blood basophils, play an important role in the development of allergies.

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