THE ADAPTIVE IMMUNE SYSTEM
III. CELL-MEDIATED IMMUNITY
B. The Steps Involved in Cell-Mediated Immunity
The overall purpose of this Learning Object is:
1) to illustrate how the body marks infected cells and tumor cells so that they can be recognized as foreign and destroyed by cytotoxic T-lymphocytes during cell-mediated immunity; and
2) understand the steps and immune cellular interactions involved between antigen recognition and antigen removal during cell-mediated immunity.
Adaptive (acquired) immunity refers to antigen-specific defense mechanisms that take several days to become protective and are designed to remove a specific antigen (def). This is the immunity one develops throughout life. There are two major branches of the adaptive immune responses: humoral immunity and cell-mediated immunity.
1. humoral immunity (def): humoral immunity involves the production of antibody molecules in response to an antigen (def) and is mediated by B-lymphocytes.
2. cell-mediated immunity (def): Cell-mediated immunity involves the production of cytotoxic T-lymphocytes, activated macrophages, activated NK cells, and cytokines in response to an antigen (def) and is mediated by T-lymphocytes.
In this section we will look at the mechanism for cell-mediated immunity.
Marking an Infected Cell or a Tumor Cell for Destruction by Cytotoxic T-Lymphocytes (CTLs)
One of the body's major defenses against viruses, intracellular bacteria, and cancers is the destruction of infected cells and tumor cells by cytotoxic T-lymphocytes or CTLs (def). These CTLs are effector cells derived from T8-lymphocytes during cell-mediated immunity. Both T8-lymphocytes and CTLs produce T-cell receptors or TCRs (def) and CD8 molecules (def) that are anchored to their surface.
a. The TCRs and CD8 molecules on the surface of naive T8-lymphocytes (def)are designed to recognize peptide epitopes (def) bound to MHC-I molecules (def) on antigen-presenting cells or APCs (def).
b. The TCRs and CD8 molecules on the surface of cytotoxic T-lymphocytes (CTLs) are designed to recognize peptide epitopes bound to MHC-I molecules on infected cells and tumor cells.
During the replication of viruses and intracellular bacteria within their host cell, as well as during the replication of tumor cells, viral, bacterial, or tumor proteins in the cytosol of that cell are degraded into a variety of peptide epitopes by cylindrical organelles called proteasomes (def). Other endogenous antigens (def) such as proteins released into the cytosol (def) from the phagosomes of antigen-presenting cells, such as macrophages (def) and dendritic cells (def) as well, as a variety of the human cell's own proteins (self-proteins) are also degraded by proteasomes. As these various endogenous antigens pass through proteasomes, proteases and peptidases chop the protein up into a series of peptides, typically 8-11 amino acids long (see Fig. 5A).
A transporter protein called TAP located in the membrane of the cell's endoplasmic reticulum then transports these peptide epitopes into the endoplasmic reticulum where they bind to the grooves of various newly made MHC-I molecules. The MHC-I molecules with bound peptides are then transported to the Golgi complex and placed in exocytic vesicles. The exocytic vesicles carry the MHC-I/peptide complexes to the cytoplasmic membrane of the cell where they become anchored to its surface (see Fig. 5A). A single cell may have up to 250,000 molecules of MHC-I with bound epitope on its surface.
During cell-mediated immunity, MHC-I molecule with bound peptide on the surface of infected cells and tumor cells can be recognized by a complementary-shaped TCR/CD8 on the surface of a cytotoxic T-lymphocyte (CTL) to initiate destruction of the cell containing the endogenous antigen (see Fig. 5C).
B. The Steps Involved in Cell-Mediated Immunity
As was pointed out earlier in the introduction, there are 5 general steps in an immune response. We will now look at these steps as they apply to cell-mediated immunity.
Step 1: The antigen must encounter the antigen-presenting cells (APCs) (def), T4-lymphocytes (def), and T8-lymphocytes (def) needed for carrying out cell-mediated immunity.
Antigens encounter the APCs, B-lymphocytes, and T4-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 everchanging populations of B-lymphocytes and T4-lymphocytes as they circulate back and forth between the blood and the lymphatics.
a. If the antigen enters through the bloodstream, it encounters the APCs, B-lymphocytes, and T4-lymphocytes in the spleen (def).
b. If the antigen enters through the tissue, it is picked up by tissue fluid, enters the lymph vessels, and is carried to the lymph nodes (def) where it encounters APCs, B-lymphocytes, and T4-lymphocytes .
c. If the antigen enters the respiratory tract, it encounters APCs, B-lymphocytes, and T4-lymphocytes in the tonsils and the mucosa-associated lymphoid tissue (MALT), including the bronchial-assoxiated lymphoid tissue (BALT), the nose-assoxiated lymphoid tissue (NALT), and the larynx-assoxiated lymphoid tissue (LALT).
d. If the antigen enters the intestinal tract, it encounters APCs, B-lymphocytes, and T4-lymphocytes in the Peyer's patches and other gut-associated lymphoid tissues (GALT).
e. If the antigen enters the genitourinary tract , it encounters APCs, B-lymphocytes, and T4-lymphocytes in the mucosa-associated lymphoid tissue (MALT) found there.
f. Finally, if the antigen penetrates the skin, it encounters APCs, B-lymphocytes, and T4-lymphocytes of the skin-associated lymphoid tissue (SALT).
Step 2: Naive (def) T4-lymphocytes and naive T8-lymphocytes must recognize peptide epitopes (def) from protein antigens by means of antigen-specific receptor molecules on their surface and become activated. This is known as clonal selection (def).
T-lymphocytes refer to lymphocytes that are produced in the bone marrow but require interaction with the thymus for their maturation. The receptors on the membrane of T-lymphocytes are called T-cell receptors (def) or TCRs. They are analogous to the B-cell receptor found on B-lymphocytes, but are composed of just two glycoprotein chains, each having a variable domain and a constant domain (see Fig. 2).
Unlike B-cell receptors that can directly bind to epitopes on antigens, the T-cell receptor or TCR of most T4-lymphocytes (def) and T8-lymphocytes (def) can only recognize peptide epitopes from protein antigens presented by the body's own cells by way of special molecules called MHC molecules (def) as seen in Fig. 3. The terminal portion of the variable domains provides specificity for binding peptides (def) of protein antigens while the teminus of the constant region becomes anchored to the cytoplasmic membrane of the T-lymphocyte. (The TCRs of NKT-cells (def) can recognize epitopes of lipid or glycolipid antigens. They do this after the epitopes have been attached to CD1 molecules on antigen-presenting cells.)
1. Naive (def) T8-lymphocytes (def)
T8-lymphocytes are T-lymphocytes displaying a surface molecule called CD8 (def). T8-lymphocytes also have on their surface, T-cell receptors (TCRs) (def). The TCRs on T8-lymphocytes, in cooperation with CD8 molecules, bind peptides from endogenous antigens (def) bound to MHC-I molecules (def). The TCR recognizes the peptide while the CD8 molecule recognizes the MHC-I molecule.
During its development, each T8-lymphocyte becomes genetically programmed, by gene-splicing reactions similar to those in B-lymphocytes and T4-lymphocytes, to produce a TCR with a unique shape capable of binding epitope/MHC-I complex with a corresponding shape (see Fig. 4). It is estimated that the human body has the ability to recognize 107 or more different epitopes (def). In order to recognize this immense number of different epitopes, the body produces 107 or more distinct clones of T-lymphocytes, each with a unique T-cell receptor. In this variety of T-cell receptors there is bound to be at least one that has an epitope-binding site able to fit, at least to some degree, peptides of any antigen the immune system eventually encounters.
One of the body's major defenses against viruses, intracellular bacteria, and cancers is the destruction of infected cells and tumor cells by cytotoxic T-lymphocytes or CTLs (def). These CTLs are effector cells (def) derived from T8-lymphocytes during cell-mediated immunity. However, in order to become CTLs, naive T8-lymphocytes (def) must become activated by cytokines produced by antigen-presenting dendritic cells. This interaction between APCs and naive T8-lymphocytes occurs primarily in the lymph nodes, the lymph nodules, and the spleen. The process can be summarized as follows:
1. In addition to microbes, dendritic cells and macrophages also engulf and degrade infected cells, tumor cells, and the remains of killed infected and tumor cells. It is thought that in this manner, endogenous antigens from other cells are able to enter the APC. During phagocytosis, some proteins are released from the phagosomes into the cytosol of the APC.
2. These cytosolic proteins then pass through proteasomes (def), where proteases and peptidases chop the protein up into a series of peptides, typically 8-11 amino acids long (see Fig. 5).
3. A transporter protein called TAP located in the membrane of the cell's endoplasmic reticulum then transports these peptide epitopes into the endoplasmic reticulum where they bind to the grooves of various newly made MHC-I molecules (see Fig. 5).
4. The MHC-I molecules with bound peptides are then transported to the Golgi complex and placed in exocytic vesicles(see Fig. 5).
5. The exocytic vesicles carry the MHC-I/peptide complexes to the cytoplasmic membrane of the cell where they become anchored to its surface (see Fig. 5). A single cell may have up to 250,000 molecules of MHC-I with bound epitope on its surface.
During this process the dendritic cells usually enter lymph vessels and are carried to regional lymph nodes. By the time they enter the lymph nodes, they have matured and are now able to present antigen to the everchanging populations of naive T8-lymphocytes passing through the lymph nodes. (Dendritic cells are also able to present antigens to naive T8-lymphocytes in other lymphoid organs such as the spleen and lymph nodules.)
The MHC-I molecules (def) with bound peptide on the surface of the dendritic cells can now be recognized by naive T8-lymphocytes possessing TCRs (def) and CD8 molecules (def) with a complementary shape (see Fig. 6). This recognition of the peptide epitope by the TCR serves as a first signal for activating the naive T8-lymphocyte for cell-mediated immunity function (def).
- To view an electron micrograph of a dendritic cell presenting antigen to T-lymphocytes, #1 see the Web page for the University of Illinois College of Medicine.
- To view an electron micrograph of a dendritic cell presenting antigen to T-lymphocytes, #2 see the Web page for the University of Illinois College of Medicine.
- Scanning electron micrograph of a dendritic cell interacting with a T-lymphocyte from sciencephotogallery.com.
Co-stimulatory signals involving the interaction of accessory molecules (def)on the APC, such as B7-1, B7-2, and LFA-3 with their corresponding ligands on the T8-lymphocyte are also necessary for activation (see Fig. 7). These co-stimulatory molecules are only synthesized when toll-like receptors on APCs bind to pathogen-associated molecular patterns of microbes (see Fig. 8).
These various molecular interactions between the dendritic cell and the T8-lymphocyte produce signals and cytokines for the activation of the naive (def) T8-lymphocyte. Once activated, signals and cytokines from effector T4-lymphocytes, primarily Th1 cells, will subsequently be able to activate transcription factors in the T8-lymphocyte that turn on genes responsible for the proliferation of that T8-lymphocyte and its differentiation into an effector cell called a cytotoxic T-lymphocyte (CTL) (def).
2. Recognition of epitopes by naive (def) T4-lymphocytes. (Effector T4-lymphocytes are needed for cell-mediated immunity.)
In order for naive T4-lymphocytes and T8-lymphocytes to proliferate, differentiate, and mount a cell-mediated response against peptide antigens these T-lymphocytes must interact with effector T4-lymphocytes.
During its development, each T4-lymphocyte becomes genetically programmed by gene-splicing reactions similar to those in B-lymphocytes, to produce a T-cell receptor or TCR (def) with a unique specificity. Identical molecules of that TCR are placed on its surface where they are able to bind an epitope/MHC-II complex with a corresponding shape on a dendritic cell. It is estimated that the human body has the ability to recognize 107 or more different epitopes (def). In order to recognize this immense number of different epitopes, the body produces 107 or more distinct clones of T-lymphocytes, each with a unique TCR. In this variety of T-cell receptors there is bound to be at least one that has an epitope-binding site able to fit, at least to some degree, peptides of any antigen the immune system eventually encounters.
Effector T4-lymphocytes (def) are cells the body uses to regulate both humoral immunity and cell-mediated immunity, however in order to do so, naive T4-lymphocytes must first become activated by cytokines (def) produced by antigen-presenting cells (APCs), mainly dendritic cells. This interaction between dendritic cells and naive T4-lymphocytes occurs primarily in the lymph nodes, the lymph nodules, and the spleen to where the antigens are transmitted from their portal of entry. The process can be summarized as follows:
1. Dendritic cells (def) located throughout the epithelium of the skin, the respiratory tract, and the gastrointestinal tract engulf exogenous antigens (def) through pinocytosis and phagocytosis. The microbes are engulfed and placed in a phagosome (def).
2. Lysosomes (def) fuse with the phagosome forming an phagolysosome having an acidic pH and proteolytic enzymes.
3. Protein antigens from the microbe are degraded by proteases into a series of peptides, from 10-30 amino acids long (see Fig. 1).
4. MHC-II molecules (def) are synthesized in the endoplasmic reticulum and transported to the Golgi complex. Once assembled, within the endoplasmic reticulum, a protein called the invarient chain (Ii) attaches to the the peptide-binding groove of the MHC-II molecules and in this way prevents peptides designated for binding to MHC-I
molecules within the ER from attaching to the MHC-II (see Fig. 1).5. The MHC-II molecules with bound Ii chain are now transported to the Golgi complex (see Fig. 1).
6. The Golgi complex places the MHC-II molecules with bound Ii chain into vesicles (see Fig. 1).
7. The vesicles containing the MHC-II molecules fuse with the peptide-containing phagolysosomes. The Ii chain is removed and the peptides are now free to bind to the grooves of the MHC-II molecules (see Fig. 1).
8. The MHC-II molecules with bound peptides are transported to the cytoplasmic membrane where they become anchored.
During this process the dendritic cells usually enter lymph vessels and are carried to regional lymph nodes. By the time they enter the lymph nodes, they have matured and are now able to present antigen to the everchanging populations of naive T4-lymphocytes passing through the lymph nodes as they circulate back and forth between the blood and the lymphatics. (Dendritic cells are also able to present antigens to naive T4-lymphocytes in other lymphoid organs such as the spleen and lymph nodules.)
Once the dendritic cells have entered the secondary lymphoid organs, the naiveT4-lymphocytes circulating through the lymphatics scour the dendritic cells by way of their specific TCRs (def) and CD4 molecules (def) looking for a peptide and MHC-II complex on the dendritic cell that has a complementary shape (see Fig. 2). This recognition of the peptide epitope by the TCR serves as a first signal for activating the naive T4-lymphocyte in order to carry out helper effector function.
- To view an electron micrograph of a dendritic cell presenting antigen to T-lymphocytes, #1 see the Web page for the University of Illinois College of Medicine.
- To view an electron micrograph of a dendritic cell presenting antigen to T-lymphocytes, #2 see the Web page for the University of Illinois College of Medicine.
- Scanning electron micrograph of a dendritic cell interacting with a T-lymphocyte from sciencephotogallery.com.
Co-stimulatory signals involving the interaction of accessory molecules on the APC, such as B7-1, B7-2, and LFA-3 with their corresponding ligands on the T4-lymphocyte are also necessary for activation (see Fig. 3).
These various molecular interactions that occur at the synapse between the dendritic cell and the T4-lymphocyte allows for the exchange of signals and cytokines for the activation of the naive T4-lymphocyte. The signals and cytokines from the dendritic cell activate transcription factors in the T4-lymphocyte that bind to and activate genes responsible for the proliferation of that T4-lymphocyte (see step 3) and its differentiation into an effector T4-lymphocyte (def); see step 4.
Step 3: After activation, the T4-lymphocytes and T8-lymphocytes must proliferate into large clones of identical cells in order to provide enough lymphocytes for an effective immune response against that antigen. This is known as clonal expansion (def).
The activated T4-helper lymphocytes from the step 2 now produce both a cytokines such as interleukin-2 (IL-2) and its corresponding receptor, IL-2 receptor (see Fig. 12). The secreted IL-2 now binds to IL-2 receptor on the T4-helper lymphocyte enabling it to proliferate into large clones of T4-helper lymphocytes.
Before an antigen enters the body, the number of naive T4-lymphocytes specific for any particular antigen is between 1 in 105 to 106 lymphocytes. After antigen exposure, the number of T4-lymphocytes specific for that antigen may increase to 1 in 100 to 1000 lymphocytes.
The IL-2 molecules and other cytokines secreted by effector T4-lymphocytes also bind to their corresponding receptors on the activated T8-lymphocyte (see Fig. 13), enabling them to proliferate and produce large clones of identical T8-lymphocytes (see Fig. 14).
Before an antigen enters the body, the number of naive T8-lymphocytes specific for any particular antigen is between 1 in 105 to 106 lymphocytes. After antigen exposure, the number of T4-lymphocytes specific for that antigen may increase to 1 in 10.
Progeny of the original lymphocytes leave the secondary lymphoid organs and migrate to tissues where they continue to respond to the invading antigen as long as it is present.
4. The large clones of T4-lymphocytes and T8-lymphocytes now differentiate into effector cells (def) capable of directing body defenses against the original antigen resulting in its destruction or removal.
a. T4-lymphocytes
Activated T4-lymphocytes undergo antigen-driven differentiation into effector cells.Functionally, there are many different types or subpopulations of effector T4-lymphocytes (def) based on the cytokines they produce. These effector T4-lymphocytes are called T helper or Th cells. They possess T-cell receptors (def) and CD4 molecules (def) on their surface. (In addition to T4-lymphocytes, certain T8-lymphocytes can function as Th cells.) Chronic immune reactions are typically dominated by three primary types: Th1-, Th2-, and Th17-lymphocytes. Th1 lymphocytes are the primary helper cells for cell-mediated immunity.
Th1 lymphocytes (def)
Th1-lymphocytes recognize antigens presented by macrophages and function primarily to activate and heighten cell-mediated immunity by producing cytokines such as interleukin-2 (IL-2), interferon-gamma (IFN-gamma), lymphotoxin, and tumor necrosis factor-beta (TNF-beta). Collectively these cytokines enables T8-lymphocytes to proliferate and differentiate into cytotoxic T-lymphocytes capable of destroying infected host cells and mutant cells, activate cytotoxic T-lymphocytes and NK cells, promote the replication of T4-lymphocytes, activate macrophages enabling them to destroy intracellular pathogens, stimulate the production of opsonizing and complement-activating antibodies for enhanced attachment during phagocytosis, activate neutrophils, stimulate increased production of monocytes in the bone marrow, allow for activation of adhesion molecules during diapedesis, and function as chemoattractants for phagocytes.
When T8-lymphocytes use their TCR and CD8 molecules to bind to peptide/MHC-1 complexes on dendritic cells and co-stimulators on dendritic cells subsequently interact with their corresponding ligands on the T8-lymphocytes, cytokines produced by the dendritic cells trigger the differentiation of the T8-lymphocytes into effector cells called cytotoxic T-lymphocytes or CTLs (def). Alternately, cytokines from Th1 cells can also enable the proliferating T8-lymphocytes to eventually differentiate into many cytotoxic T-lymphocytes, as well as T8-memory cells.
The cytotoxic T-lymphocytes can now bind to and kill the virus-infected cell by inducing apoptosis (def) (see Fig. 15 and Fig. 16), a programmed suicide of the infected cell that will be discussed in greater detail in the next section of this unit.
Effector T8-lymphocytes, effector T4-lymphocytes, and APCs also secrete a variety of cytokines (def) which influence the activity of a variety of body defense cells as well as promote various nonspecific body defenses such as inflammation and fever. These will also be discussed in greater detail below.
5. Some of the lymphocytes differentiate into circulating T4-memory cells, T8-memory cells, and T-regulatory cells.
Circulating T4-memory cells and T8-memory cells (def) allow for a more rapid and greater production of CTLs and cytokines upon subsequent exposure to the same antigen.
The T-regulatory cells (T-reg cells) help to regulate adaptive immune responses by suppressing the function of effector T-lymphocytes, helping to combat autoimmunity, and promoting anamnestic response in order to resist repeat infections. (Natural killer T-lymphocytes (NKT-cells) also seem to play a role in regulating immunity by suppressing autoimmune diseases and inducing transplantation tolerance.)
All of these events occur in the lymphoid tissue. From the lymphatics, the CTLs and effector T4-lymphocytes enter the bloodstream where they can be delivered anywhere in the body via the circulatory system and the inflammatory response.
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