THE ADAPTIVE IMMUNE SYSTEM
III. CELL-MEDIATED IMMUNITY
A. An Overview
The overall purpose of this Learning Object is to introduce cytotoxic T-lymphocytes, macrophages, NK cells, and cytokines and their role in cell-mediated immunity.
LEARNING OBJECTIVES FOR THIS SECTION
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 and at how cell-mediated immunity helps to defend the body.
A. Cell Mediated Immunity: An Overview
Cell-mediated immunity (CMI) is an immune response that does not involve antibodies but rather involves the activation of macrophages and NK-cells, the production of antigen-specific cytotoxic T-lymphocytes (def), and the release of various cytokines (def) in response to an antigen (def). Cellular immunity protects the body by:
1. activating antigen-specific cytotoxic T-lymphocytes (CTLs) that are able to destroy body cells displaying epitopes of foreign antigen on their surface, such as virus-infected cells, cells with intracellular bacteria, and cancer cells displaying tumor antigens;
2. activating macrophages and NK cells, enabling them to destroy intracellular pathogens; and
3. stimulating cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive immune responses and innate immune responses.
Cell-mediated immunity is directed primarily microbes that survive in phagocytes and microbes that infect non-phagocytic cells. It is most effective in destroying virus-infected cells, intracellular bacteria, and cancers. It also plays a major role in delayed transplant rejection.
1. Generation of T-cell receptor (TCR) diversity through gene translocation
As mentioned earlier, the immune system of the body has no idea as to what antigens it may eventually encounter. Therefore, it has evolved a system that possesses the capability of responding to any conceivable antigen. The immune system can do this because both B-lymphocytes and T-lymphocytes have evolved a unique system of gene-splicing called gene translocation (def) , a type of gene-shuffling process where various different genes along a chromosome move and join with other genes from the chromosome.
To demonstrate this gene translocation process, we will look at how each T-lymphocyte becomes genetically programmed to produce a T-cell receptor (TCR) having a unique shape to fit a specific epitope.
In a manner similar to B-lymphocytes, T-lymphocytes are able to cut out and splice together different combinations of genes along their chromosomes. Through random gene translocation, any combination of the multiple forms of each gene can join togethe.This is known as combinatorial diversity.
The T-cell receptors or TCRs (see Fig. 1) of most T-lymphocytes involved in adaptive immunity consist of an alpha(α) and a beta (β)chain. There are 70-80 different Vα genes and 61 different Jα genes that code for the variable portion of the α chain of the TCR. Likewise, there are 52 Vβ genes, 1 Dβ1 gene, 1 Dβ2 gene, and 6-7 Jβ genes that can recombine to form the variable portion of the TCR.
During gene translocation, specialized enzymes in the T-lymphocyte cause splicing inaccuracies wherein additional nucleotides are added or deleted at the various gene junctions. This change in the nucleotide base sequence generates even greater diversity in Fab shape. This is called junctional diversity. Unlike the BCR, somatic hypermutation does not occur during the production of the TCRs.
As a result of combinatorial diversity and junctional diversity, each T-lymphocyte is able to produce a unique shaped T-cell receptor (TCR) capable of reacting with complementary-shaped peptide bound to a MHC molecule.
2. Anamnestic Response (Memory)(def)
As a result of T-lymphocytes recognizing epitopes of protein antigens during cell-mediated immunity, numerous circulating T8-memory cells and T4-memory cells (def) developwhich possess anamnestic response or memory. These T-memory cells persist for the remainder of a person’s life. (During humoral immunity, B-memory cells also develop as learned under humoral immunity.)
A subsequent exposure to that same antigen results in:
- A more rapid and longer production of cytotoxic T-lymphocytes (CTLs); and
- A more rapid and longer production of T4-effector lymphocytes
3. Clonal Selection (def) and Clonal Expansion(def)
As mentioned above, during early differentiation of naive T-lymphocytes in the thymus marrow, each T4-lymphocyte (def) and each T8-lymphocyte (def) becomes genetically programmed to make a T-cell receptor or TCR (def) with a unique shape through a series of gene translocations, and molecules of that TCR are put on its surface of that T-lumphocyte to function as its epitope receptor. When an antigen encounters the immune system, epitopes from protein antigens bound to MHC-I (def) or MHC-II (def) molecules eventually will react with a naive T4- and T8-lymphocyte (def) with TCRs and CD4 (def) or CD8 (def) molecules on its surface that more or less fit and this activates that T-lymphocyte. This process is known as clonal selection.
Cytokines (def) produced by effector T4-helper lymphocytes (def) enable the now activated T4- and T8-lymphocyte to rapidly proliferate to produce large clones of thousands of identical T4- and T8-lymphocytes. In this way, even though only a few T-lymphocytes in the body may have TCR molecule able to fit a particular epitope, eventually many thousands of cells are produced with the right specificity. This is referred to as clonal expansion. These cells then differentiate into effector T4-lymphocytes and cytotoxic T-lymphocytes or CTLs (def).
Cellular immunity is also the mechanism behind delayed hypersensitivity (discussed later in this unit). Delayed hypersensitivity (def) is generally used to refer to the harmful effects of cell-mediated immunity (tissue and transplant rejections, contact dermatitis, positive skin tests like the PPD test for tuberculosis, granuloma formation during tuberculosis and deep mycoses, and destruction of virus-infected cells).
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