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12.5: An Overview of the Steps Involved in Adaptive Immune Responses

Skills to Develop

  1. List the 5 general steps involved in the immune responses in their correct order.
  2. State where antigens may encounter APCs, B-lymphocytes, and T-lymphocytes if they enter the following:
    1. the blood
    2. tissues
    3. the respiratory tract
    4. the gastrointestinal tract
    5. the genitourinary tract
  3. Briefly describe how the receptor molecules on the surface of naive B-lymphocytes, T4-helper lymphocytes, and T8-lymphocytes eventually recognize or bind epitope, indicating the roles of BCR, TCR, CD4, CD8, MHC-I, and MHC-II molecules in lymphocyte activation.
  4. State the overall function of T4-effector lymphocytes and the importance behind rapid proliferation of activated lymphocytes.
  5. State what types of effector cells the proliferating B-lymphocytes and T8-lymphocytes differentiate into in order to destroy or neutralize the antigen.
  6. Define cytokine.
  7. State the function of memory cells.
  8. State what is meant by immunologic tolerance.

Whether humoral immunity or cell-mediated immunity , there are several general steps involved in the immune responses.

1. The antigen must encounter the B-lymphocytes , T-lymphocytes , and antigen-presenting cells (APCs) capable of carrying out an adaptive immune response.

Fundamental Statement for this Step:

1. Antigens encounter the APCs, B-lymphocytes, and T-lymphocytes in the secondary lymphoid organs of the lymphoid system.

Antigens encounter the APCs, B-lymphocytes, and T-lymphocytes in the secondary lymphoid organs of the lymphoid system. Tissue fluid carries antigens to lymph nodes, blood carries antigens to the spleen, and immature dendritic cells under the skin and mucosal epithelium carry antigens to regional lymph nodes. Here they encounter ever changing populations of naive B-lymphocytes, T4-lymphocytes, and T8-lymphocytes as they circulate back and forth between the blood and the lymphatics.

  1. Antigens that enter through the bloodstream, encounter the APCs, B-lymphocytes, and T-lymphocytes in the spleen ; see Fig. 1.
  2. Antigens that enter through the tissue, are picked up by tissue fluid, enter the lymph vessels, and are carried to the lymph nodes where they encounter APCs, B-lymphocytes, and T-lymphocytes; see Fig. 2.
  3. Antigens that enter the respiratory tract, encounter APCs, B-lymphocytes, and T-lymphocytes in the tonsils and the mucosa-associated lymphoid tissue (MALT), including the bronchial-associated lymphoid tissue (BALT), the nose-associated lymphoid tissue (NALT), and the larynx-associated lymphoid tissue (LALT).
  4. Antigens that enter the intestinal tract, encounter APCs, B-lymphocytes, and T-lymphocytes in the Peyer's patches (see Fig. 3) and other gut-associated lymphoid tissues (GALT).
  5. Antigens that enter the genitourinary tract , encounter APCs, B-lymphocytes, and T-lymphocytes in the mucosa-associated lymphoid tissue (MALT) found there.
  6. Finally, antigens that penetrate the skin, encounter APCs, B-lymphocytes, and T-lymphocytes of the skin-associated lymphoid tissue (SALT).

 

2. Naive B-lymphocytes, T4-lymphocytes, and T8-lymphocytes must recognize epitopes of an antigen by means of antigen-specific receptor molecules on their surface and become activated. This is known as clonal selection.

Fundamental Statements for this Step:

1. Dendritic cells bind peptide epitopes to MHC-II molecules to enable them to be recognized by complementary shaped T-cell receptors (TCR) and CD4 molecules on naive T4-lymphocyte.
2. Dendritic cells bind peptide epitopes to MHC-I molecules to enable them to be recognized by complementary shaped T-cell receptors (TCR) and CD8 molecules on naive T8-lymphocytes.
3. These interactions are required to enable the T4-lymphocyte or T8-lymphocyte to become activated, proliferate, and differentiate into effector cells.
4. Naive T4-lymphocytes have T cell receptors (TCRs ) that, in cooperation with CD4 molecules, bind to MHC-II molecules with attached epitope from an antigen found on the surface of an antigen-presenting dendritic cell.
5. Naive T8-lymphocytes have T cell receptors (TCRs) that, in cooperation with CD8 molecules, bind to MHC-I molecules with attached epitope from an antigen found on the surface of antigen-presenting dendritic cells.
6. Most proteins are T-dependent antigens. In order for naive B-lymphocytes to proliferate, differentiate and mount an antibody response against T-dependent antigens, these B-lymphocytes must interact with effector T4-lymphocytes.

7. Specialized macrophages and specialized dendritic cells called FDCs are located in the lymphoid tissues. Antigens and microbes are are found on the surface of these FDCs and macrophages which present them to complementary-shaped BCRs on naive B-lymphocytes.
7. A few antigens are called T-independent antigens. T-independent (TI) antigens are usually large carbohydrate and lipid molecules with multiple, repeating subunits. B-lymphocytes mount an antibody response to T-independent antigens without the requirement of interaction with effector T4-lymphocytes but the antibody response is much more limited than with T-dependent antigens.

a. The role of antigen-presenting dendritic cells

The primary function of dendritic cells is to capture and present protein antigens to naive T-lymphocytes.

  • Dendritic cells bind peptide epitopes to MHC-II molecules (see Fig. 4) to enable them to be recognized by complementary shaped T-cell receptors (TCR) and CD4 molecules on naive T4-lymphocyte .
  • Dendritic cells bind peptide epitopes to MHC-I molecules (see Fig. 5) to enable them to be recognized by complementary shaped T-cell receptors (TCR) and CD8 molecules on naive T8-lymphocytes .

These interactions are required to enable the T4-lymphocyte or T8-lymphocyte to become activated, proliferate, and differentiate into effector cells .

Most dendritic cells are derived from monocytes and are referred to as myeloid dendritic cells. They are located under the surface epithelium of the skin and the surface epithelium of the mucous membranes of the respiratory tract, genitourinary tract, and the gastrointestinal tract. They are also found throughout the body's lymphoid tissues and in most solid organs.

Upon capturing antigens through pinocytosis and phagocytosis and becoming activated by proinflammatory cytokines, the dendritic cells detach from the epithelium, enter lymph vessels, and are carried to regional lymph nodes (see Fig. 6). By the time they enter the lymph nodes, they have matured and are now able to present antigen to the ever changing populations of naive T-lymphocytes located in the T-cell area of the lymph nodes (see Fig. 7).

b. Naive T4-helper lymphocytes recognizing peptide epitopes

Naive T4-lymphocytes circulate in the blood. In response to chemokines produced by lymphoid tissues, they leave the vascular endothelium in regions called high endothelial venules and enter lymph nodes or other secondary lymphoid tissues, a process called diapedesis .

Naive T4-lymphocytes have T-cell receptors (TCRs) that, in cooperation with CD4 molecules, bind to MHC-II molecules with attached epitope from an antigen found on the surface of an antigen-presenting dendritic cells ; (see Fig. 8). Each T4-lymphocyte is genetically programmed to make a unique TCR. The TCR recognizes the peptide while the CD4 molecule recognizes the MHC-II molecule.

 

c. Naive T8-lymphocytes recognizing peptide epitopes

Naive T8-lymphocytes circulate in the blood. In response to chemokines produced by lymphoid tissues, they leave the vascular endothelium in regions called high endothelial venules and enter lymph nodes or other secondary lymphoid tissues, a process called diapedesis .

Naive T8-lymphocytes have T-cell receptors (TCRs) that, in cooperation with CD8 molecules, bind to MHC-I molecules with attached epitope from an antigen found on the surface of antigen-presenting dendritic cells (see Fig. 9). Each T8-lymphocyte is genetically programmed to make a unique TCR. The TCR recognizes the peptide while the CD8 molecule recognizes the MHC-I molecule.

 

d. Naive B-lymphocytes recognizing epitopes of antigens

Most proteins are T-dependent antigens . In order for naive B-lymphocytes to proliferate, differentiate and mount an antibody response against T-dependent antigens, these B-lymphocytes must interact with effector T4-lymphocytes. All classes or isotypes of antibody molecules can be made against T-dependent antigens and there is usually a memory response against such antigens.

Naive B-Lymphocytes encounter antigens in secondary lymphoid organs such as the lymph nodes and the spleen. Using a lymph node as an example, soluble antigens, such as microbial polysaccharides and proteins and toxins, as well as microbes such as bacteria and viruses, enter the lymph node through afferent lymphatic vessels. By this time, complement pathway activation has coated these soluble antigens or microbes with opsonins such as C3b, which in turn can be degraded to C3d.

Located within the lymphoid tissues are specialized macrophages and specialized dendritic cells called follicular dendritic cells (FDCs). These macrophages have poor endocytic ability and produce few lysosomes. The FDCs are nonphagocytic. Both cell types, however, have complement receptors called CR1 and CR2 that bind to the C3b and C3d, enabling the antigens and microbes to stick to the surface of the macrophages and FDCs. However,because of the poor endocytic ability of the macrophages and the lack of endocytosis by the FDCs, the antigens and microbes are not engulfed but rather remain on the surface of the cells. In addition, the macrophages can transfer their bound antigens or microbes to FDCs (see Fig. 10). Here the antigens and microbes in the lymph node can bind to complementary-shaped BCRs on naive B-lymphocytes directly, by way of macrophages, or via the FDCs (see Fig. 10).

A few antigens are called T-independent antigens . T-independent (TI) antigens are usually large carbohydrate and lipid molecules with multiple, repeating subunits. B-lymphocytes mount an antibody response to T-independent antigens without the requirement of interaction with effector T4-lymphocytes . Bacterial lipopolysaccharide (LPS) from the Gram-negative cell wall and capsular polysaccharides are examples of TI antigens. The resulting antibody molecules are generally of the IgM isotype and do not give rise to a memory response. There are two basic types of T-independent antigens: TI-1 and TI-2.

1. TI-1 antigens are pathogen-associated molecular patterns or PAMPS such as lipopolysaccharide (LPS) from the outer membrane of the Gram-negative cell wall and bacterial nucleic acid. These antigens activate B-lymphocytes by binding to their specific pattern-recognition receptors , in this case toll-like receptors, rather than to B-cell receptors (see Fig. 11). Antibody molecules generated against TI-1 antigens are often called "natural antibodies" because they are always being made against bacteria present in the body.

2. TI-2 antigens, such as capsular polysaccharides, are molecules with multiple, repeating subunits. These repeating subunits activate B-lymphocytes by simultaneously cross-linking a number of B-cell receptors (see Fig. 12).

Those naive B-lymphocytes not activated by epitopes of antigens exit the lymph node or other lymphoid tissue and eventually re-enter the bloodstream.

3. After the naive B-lymphocytes, T4-lymphocytes, and T8-lymphocytes bind their corresponding epitopes, they must proliferate into large clones of identical cells in order to mount a successful immune response against that antigen. This is known as clonal expansion.

Fundamental Statements for this Step:

1. With the exception of T-independent antigens, naive B-lymphocytes must be stimulated to proliferate by means of cytokines called interleukins produced primarily by effector T4- lymphocytes such as TFH cells.
2. In the case of T4-lymphocytes and T8-lymphocytes, dendritic cells produces cytokines that contribute to proliferation of the activated T-lymphocytes. CD28-dependent co-stimulation of the T4-lymphocyte also stimulates it to synthesize the cytokine interleukin-2 (IL-2) as well as a high-affinity IL-2 receptor. The binding of IL-2 to its high affinity receptor allows for cell proliferation and formation of a clone of thousands of identical T-lymphocytes after several days.

With the exception of T-independent antigens , the naive B-lymphocytes that were activated in step 2 must be stimulated to proliferate by means of cytokines called interleukins (such as IL-2, IL-4, IL-5, Il-6, and IL-10) produced primarily by effector T4- lymphocytes such as TFH cells (see Fig. 13).

 

In the case of T4-lymphocytes and T8-lymphocytes, dendritic cells produces cytokines such as interleukin-6 (IL-6), IL-4, IL-12, and T-cell growth factor-beta (TGF-ß) that contribute to proliferation of the activated T-lymphocytes. CD28-dependent co-stimulation of the T4-lymphocyte also stimulates it to synthesize the cytokine interleukin-2 (IL-2) as well as a high-affinity IL-2 receptor. The binding of IL-2 to its high affinity receptor allows for cell proliferation and formation of a clone of thousands of identical T-lymphocytes after several days.

It is thought that in most immune responses, only around 1/1000 to 1/10,000 lymphocytes will have a receptor capable of binding the initiating antigen. Thus, proliferation allows the production of clones of thousands of identical lymphocytes having specificity for the original antigen. This is essential to give enough cells to mount a successful immune response against that antigen.

 

4. The large clones of identical B-lymphocytes, T4-lymphocytes, and T8-lymphocytes now differentiate into effector cells capable of directing body defenses against the original antigen resulting in its destruction or neutralization.

Fundamental Statements for this Step:

1. Cytokines produced by dendritic cells and T4-effector lymphocytes enable the clones of B-lymphocytes and T-lymphocytes above to differentiate into effector cells.
2.
In the case of humoral immunity, B-lymphocytes differentiate into effector cells called plasma cells. These cells synthesize and secrete vast quantities of antibodies capable of reacting with and eliminating or neutralizing the original antigen.
3. T4-lymphocytes differentiate into T4-effector lymphocytes.
Functionally, there are many different types or subpopulations of effector T4-lymphocytes based on the cytokines they produce. Examples include TH1 cells, TH2 cells, TH17 cells, Treg cells, and TFH cells.
4. In the case of cell-mediated immunity , the T8-lymphocytes differentiate into cytotoxic T-lymphocytes (CTLs) capable of destroying body cells having the original epitope on their surface, such as viral infected cells, bacterial infected cells, and tumor cells by inducing apoptosis.
5. Antibodies, cytokines, activated macrophages, and cytotoxic T-lymphocytes eventually destroy or remove the antigen.

Cytokines produced by dendritic cells and T4-effector lymphocytes enable the clones of B-lymphocytes and T-lymphocytes from step 3 above to differentiate into effector cells.

a. In the case of humoral immunity , B-lymphocytes differentiate into effector cells calledplasma cells . These cells synthesize and secrete vast quantities of antibodies capable of reacting with and eliminating or neutralizing the original antigen (see Fig. 14).

b. T4-lymphocytes differentiate into T4-effector lymphocytes . Functionally, there are many different types or subpopulations of effector T4-lymphocytes based on the cytokines they produce. Immune reactions are typically dominated by five primary types: TH1 cells, TH2 cells, TH17 cells, Treg cells, and TFH cells.

1. CD4 TH1 cells: Coordinate immunity against intracellular bacteria and promote opsonization. They:

  • Produce cytokines such as interferon-gamma (IFN-?) that promote cell-mediated immunity against intracellular pathogens, especially by activating macrophages that have either ingested pathogens or have become infected with intracellular microbes such as Mycobacterium tuberculosis, Mycobacterium leprae, Leishmania donovani, and Pneumocystis jiroveci that are able to grow in the endocytic vesicles of macrophages. Activation of the macrophage by TH1 cells greatly enhances their antimicrobial effectiveness.
  • They produce cytokines that promote the production of opsonizing antibodies that enhance phagocytosis (see Fig. 15).
  • Produce receptors that bind to and kill chronically infected cells, releasing the bacteria that were growing within the cell so the can be engulfed and killed by macrophages.
  • Produce the cytokine interleukin-2 (IL-2) that induces T-lymphocyte proliferation.
  • Produce cytokines such as tumor necrosis factor-alpha (TNF-a) that promote diapedesis of macrophages.
  • Produces the chemokine CXCL2 to attract macrophages to the infection site.
  • Produce cytokines that block the production of TH2 cells.

2. CD4 TH2 cells: Coordinate immunity against helminths and microbes that colonize mucous membranes

  • Produce the cytokine interleukin-4 (IL-4) that promotes the production of the antibody isotype IgE in response to helminths and allergens . IgE is able to stick eosinophils to helminths for extracellular killing of the helminth (see Fig. 16); it also promotes many allergic reactions.
  • Produce cytokines that attract and activate eosinophils and mast cells.
  • Promote the production of antibodies that neutralize microbes (see Fig. 17) and toxins (see Fig. 18) preventing their attachment to host cells.
  • Produce cytokines that function as B-lymphocyte growth factors such as IL-4, IL-5, IL-9. and IL-13 (see Fig. 13).
  • Produce interleukin-22 (IL-22) that promotes the removal of microbes in mucosal tissues.
  • Produce cytokines that block the production of TH1 cells.

3. CD4 TH17 cells: Promote a local inflammatory response to stimulate a strong neutrophil response and promote the integrity of the skin and mucous membranes

  • Produce cytokines like interleukin-17 (IL-17) and interleukin-6 (IL-6) that trigger local epithelial cells and fibroblasts to produce chemokines that recruit neutrophils to remove extracellular pathogens.

4. CD4 Treg cells: Suppress immune responses

  • Produce inhibitory cytokines such as Interleukin-10 (IL-10) and TGF-ß that help to limit immune responses and prevent autoimmunity by suppressing T-lymphocyte activity.
  • Promoting anamnestic response (immunologic memory) to resist repeat infections by the same microbe.
  • Protecting beneficial normal flora in the intestines from being destroyed by the immune system.
  • Aiding in sustaining pregnancy so that the immune system doesn't recognize a fetus as foreign and try to destroy it.
  • Controlling established inflammation in tissues.

5. TFH cells: Promote humoral immunity by stimulating antibody production and antibody isotype switching by B-lymphocytes

  • T follicular helper cells (TFH cells) are located in lymphoid follicles.
  • TFH cells are now thought to be the primary effector T-lymphocytes that stimulate antibody production and isotype switching by B-lymphocytes. They are able to produce cytokines that are characteristic of both TH2 cells and TH1 cells.
  • TFH cells producing (IFN-?) promote the production of opsonizing antibodies; those producing IL-4 promote the production of IgE.

c. In the case of cell-mediated immunity , the T8-lymphocytes differentiate into cytotoxic T-lymphocytes (CTLs) capable of destroying body cells having the original epitope on their surface, such as viral infected cells, bacterial infected cells, and tumor cells. They do this by inducing apoptosis , a programmed cell suicide (see Fig. 19 and Fig. 20). T-lymphocytes also secrete various cytokines that participate in various aspects of adoptive and innate immunity.

Progeny of the original lymphocytes leave the secondary lymphoid organs and migrate to tissues where they continue to respond to the invading antigen.

Antibodies, cytokines, activated macrophages, and cytotoxic T-lymphocytes eventually destroy or remove the antigen. Antibodies and cytokines amplify defense functions and collaborate with cells of the innate immune system, such as phagocytes and NK cells , as well as with molecules of the innate immune system, such as those of the complement system and the acute phase response . Cytotoxic T-lymphocytes (CTLs) destroy body cells having the original epitope on their surface, e.g., viral infected cells, bacterial infected cells, and tumor cells. Cytokines also amplify innate immune defenses such as inflammation , fever, and the acute phase response.

5. Some of the B-lymphocytes, T4-lymphocytes, and T8-lymphocytes differentiate into long-lived, circulating memory cells .

Fundamental Statements for this Step:

1. During the proliferation and differentiation that follows lymphocyte activation, some of the B-lymphocytes and T-lymphocytes stop replicating and become circulating, long-lived memory cells.
2.
Memory cells are capable of what is called anamnestic response or "memory", that is, they "remember" the original antigen. If that same antigen again enters the body while the memory cells are still present, these memory cells will initiate a rapid, heightened secondary response against that antigen.

During the proliferation and differentiation that follows lymphocyte activation, some of the B-lymphocytes and T-lymphocytes stop replicating and become circulating, long-lived memory cells. Memory cells are capable of what is called anamnestic response or "memory", that is, they "remember" the original antigen. If that same antigen again enters the body while the memory cells are still present, these memory cells will initiate a rapid, heightened secondary response against that antigen (see Fig. 14 and Fig. 21).

This is why the body sometimes develops a permanent immunity after an infectious disease and is also the principle behind immunization.

Immune Regulation

Fundamental Statements for this Process:

1. The immune responses are carefully regulated by a variety of mechanisms. They are turned on only in response to an antigen and are turned off once the antigen has been removed.
2. The immune responses are also able to discriminate between self and non-self in order to prevent autoimmune tissue damage.
3. During the random gene-splicing reactions mentioned earlier, some lymphocytes are bound to produce receptors that fit the body's own proteins and polysaccharides. The body develops immunologic tolerance to these self antigens by triggering apoptosis in self-reactive lymphocytes.
4. Alternately, immature B-lymphocytes with self-reactive B-cell receptors may be stimulated to undergo a new gene rearrangement to make a new receptor that is no longer self-reactive. This process is called receptor editing.
5. Some autoreactive T-lymphocytes are able to slip through the system but a group of T4-effector lymphocytes called Treg cells are able to suppress their action.
7. If there is a breakdown in this normal elimination or suppression of self-reacting cells, autoimmune diseases may develop.

The immune responses are carefully regulated by a variety of mechanisms. They are turned on only in response to an antigen and are turned off once the antigen has been removed.

The immune responses are also able to discriminate between self and non-self in order to prevent autoimmune tissue damage. During the random gene-splicing reactions mentioned earlier, some lymphocytes are bound to produce receptors that fit the body's own proteins and polysaccharides. Through mechanisms that are not fully understood, the body develops immunologic tolerance to these self antigens. In other words, the immune system becomes tolerant of the body's own molecules.

During lymphocyte development, the body eliminates self-reactive lymphocytes. Self-reactive B-lymphocytes undergo negative selection. Since the bone marrow, where the B-lymphocytes are produced and mature, is normally free of foreign substances, any B-lymphocytes that bind substances there must be recognizing "self" and are eliminated by apoptosis , a programmed cell suicide. Apoptosis results in the activation of proteases within the target cell which then degrade the cell's structural proteins and DNA. Alternately, immature B-lymphocytes with self-reactive B-cell receptors may be stimulated to undergo a new gene rearrangement to make a new receptor that is no longer self-reactive. This process is called receptor editing .

This negative selection also occurs in secondary lymphoid organs whenever a T-dependent B-lymphocyte binds to an antigen but is then unable to react with its specific T-4 lymphocyte because the T4-lymphocyte does not recognize that antigen as foreign.

Self-reactive T-lymphocytes undergo both negative selection and positive selection. Positive selection occurs in the thymus and eliminates T-lymphocytes that cannot recognize MHC molecules . Because T4-lymphocytes and T8-lymphocytes can only recognize peptide epitopes bound to MHC molecules, any T-lymphocytes that cannot recognize MHC molecules fail this positive selection, do not develop any further, and are eventually eliminated. Then, each T-lymphocyte that passes positive selection by being able to recognize a MHC molecule must undergo negative selection. Any T-lymphocytes recognizing "self" peptides bound to MHC molecules are eliminated by apoptosis. Like with B-lymphocytes, this negative selection also occurs in secondary lymphoid organs whenever a T-lymphocyte binds to a peptide on a MHC molecule but is then unable to react with its specific T-4 lymphocyte because the T4-lymphocyte does not recognize that peptide as foreign.

Some autoreactive T-lymphocytes are able to slip through the system but a group of T4-effector lymphocytes called Treg cells are able to suppress their action. If there is a breakdown in this normal elimination or suppression of self-reacting cells, autoimmune diseases may develop.

We will now look at the various events discussed above in greater detail as they apply to both humoral immunity and cell-mediated immunity with special emphasis on infectious diseases. Keep in mind that some infectious agents live outside human cells (e.g., most bacteria), a few live inside the phagosomes and lysosomes of human cells through which they enter (e.g., Mycobacterium tuberculosis, Mycobacterium leprae), and others live in the fluid interior of human cells (e.g., viruses, Rickettsias, and Chlamydias). Through a combination of humoral immunity and cell-mediated immunity, all types of infectious agents, as well as many types of tumor cells, may be eliminated from the body.

Contributors

  • Dr. Gary Kaiser (COMMUNITY COLLEGE OF BALTIMORE COUNTY, CATONSVILLE CAMPUS)