Cell-Mediated Immunity

Definition of Cell-Mediated Immunity

Cell-mediated immunity (CMI) is an immune response that does not involve antibodies
but rather involves activation of macrophages and NK cells, production of antigen-
specific cytotoxic T lymphocytes, and release of various cytokines in response to
antigens. . Cellular immunity protects the body by:

1. Activate antigen-specific cytotoxic T lymphocytes (CTLs) which are

capable of destroying body cells displaying foreign antigen epitopes on
their surface, such as virus-infected cells, cells with intracellular bacteria,
and cancer cells displaying tumor antigens;

2. Activates macrophages and NK cells, enabling them to destroy intracellular

pathogens; And

3. Stimulating cells to secrete various cytokines that affect the function of

other cells involved in adaptive immune response and innate immune
response.

Cell-mediated immunity is directed primarily at microbes that survive on phagocytes

and microbes that infect non-phagocytic cells. It is most effective in destroying cells
infected with viruses, intracellular bacteria and cancer. It also plays a major role in
delayed transplant rejection.
 Generation of T-cell receptor diversity (TCR)
via gene translocation
As previously mentioned, the immune system does not know what antigen it will
eventually encounter. Therefore, a system has been developed which has the ability to
respond to any imaginable antigen. The immune system is able to do this because B
lymphocytes and T lymphocytes have developed a unique gene splicing system called
gene translocation, a type of gene shuffling process in which different genes along a
chromosome move around and join with other genes off the chromosome. To
demonstrate this process of gene translocation, we will see how each T-lymphocyte is
genetically programmed to produce a T-cell receptor (TCR) that has a unique shape to
match a particular epitope.

In a similar way to B-lymphocytes, T-lymphocytes are able to cut and splice different
combinations of genes along their chromosomes. Through random gene translocations,
any combination of different forms of each gene can join together. This is known as
combinatorial diversity. The T cell receptors or TCRs (Fig. \(\PageIndex{1}\)) of most T
lymphocytes involved in adaptive immunity consist of alpha (a) and beta (ß) chains.
There are 70–80 different Va genes and 61 different Ja genes that encode the variable
part of the a TCR chain. Similarly, there are 52 V ß genes, 1 D ß1 gene, 1 D ß2 gene,
and 6-7 J ß14.1. 114.1.1 ) Most of the T-lymphocytes involved in adaptive immunity
consist of alpha (a) and beta (ß) chains. There are 70-80 V of different genes which can
recombine to form the variable part of the TCR.
T. Most T-cell receptors consist of two polypeptide chains, an alpha (α) chain and a
beta (β) chain. The variable domains of the α and β chains (red) provide specificity for
binding to peptides bound to MHC molecules. The constant end domain (purple)
anchors the receptor to the T-lymphocyte cytoplasmic membrane. (SS = disulfide
bond)14.1. 114.1.1 : T-Cell Receptors. Most T-cell receptors consist of two polypeptide
chains, an alpha (α) chain and a beta (β) chain. The variable domains of the α and β
chains (red) provide specificity for binding to peptides bound to MHC molecules. The
constant end domain (purple) anchors the receptor to the T-lymphocyte cytoplasmic
membrane. (SS = disulfide bond)

During gene translocation, special enzymes in T-lymphocytes cause splicing inaccuracies

where additional nucleotides are added or removed at various gene junctions. This
change in the nucleotide base sequence results in a greater diversity in the shape of the
Fab. This is called functional diversity. In contrast to BCR, somatic hypermutation does
not occur during TCR production. As a result of combinatorial diversity and junctional
diversity, each T-lymphocyte is capable of generating a uniquely shaped T-cell receptor
(TCR) capable of reacting with complementary shaped peptides bound to MHC
molecules.

Response Anamnesis (Memory)

As a result of T lymphocytes recognizing protein antigen epitopes during cell-mediated
immunity, many circulating T8 memory cells and T4 memory cells develop that have
anamnestic responses or memories. These T-memory cells last for the rest of a person's
life. Effector memory T cells (EM T cells) circulate in the blood whereas tissue resident
memory T cells (RM T cells) are found in the epithelium of the skin and mucous
membranes. CD8 T RM cells are normally activated by viral antigens and subsequently
produce inflammatory cytokines that trigger an innate immune response for nonspecific
antiviral activity. CD4 T RMcells are found in groups surrounding macrophages in the
mucosa. Unlike EM T cells, RM T cells do not circulate in the blood and are not
replenished from the blood. They remain in the peripheral tissues.

Subsequent exposure to the same antigen results in:

• Faster and longer production of cytotoxic T lymphocytes (CTLs);

• Faster and longer production of T4 effector lymphocytes; And

• Triggers a nonspecific innate immune response.

 Clone Selection and Clone Expansion
As mentioned above, during the initial differentiation of naïve T lymphocytes in the
thymus marrow, every T4 lymphocyte and every T8 lymphocyte is genetically
programmed to make a T cell receptor or TCR with a unique shape through a series of
gene translocations, and those TCR molecules are deposited on the surface of T-
lymphocytes. it is to function as its receptor epitope. When the antigen encounters the
immune system, the epitopes of the antigen proteins bound to MHC-I or MHC-II
molecules will eventually react with naïve T4- and T8 lymphocytes with TCR and CD4 or
CD8 molecules on their more or less suitable surface and this activates T. -the
lymphocyte. This process is known as clonal selection.

Cytokines produced by effector T4-helper lymphocytes allow the now activated T4 and
T8 lymphocytes to multiply rapidly to produce large clones of thousands of identical T4
and T8 lymphocytes. In this way, although only a few T-lymphocytes in the body may
have TCR molecules capable of conforming to a particular epitope, thousands of cells
end up being produced with the proper specificity. This is referred to as clonal
expansion. These cells then differentiate into effector T4 lymphocytes and cytotoxic T
lymphocytes or CTLs.

Cellular immunity is also the mechanism behind delayed hypersensitivity (discussed

later in this unit). Delayed hypersensitivity is commonly used to refer to the harmful
effects of cell-mediated immunity (tissue and transplant rejection, contact dermatitis,
positive skin tests such as the PPD test for tuberculosis, granuloma formation during
tuberculosis and deep mycosis, and destruction of virus-infected cells).

Summary
1. Cell-mediated immunity (CMI) is an immune response that does not involve
antibodies but instead involves activation of macrophages and NK cells,
production of antigen-specific cytotoxic T lymphocytes, and release of various
cytokines in response to antigens. .

2. Cell-mediated immunity is directed primarily at microbes that survive on

phagocytes and microbes that infect non-phagocytic cells. It is most effective in
destroying cells infected with viruses, intracellular bacteria and cancer.
3. In a similar way to B lymphocytes, T lymphocytes can randomly cut and splice
different combinations of genes along their chromosomes through a process
called gene translocation. This is known as combinatorial diversity and results in
each T-lymphocyte producing a unique T-cell receptor (TCR).

4. During gene translocation, special enzymes in T-lymphocytes cause splicing

inaccuracies where additional nucleotides are added or deleted at various gene
splices. This change in the nucleotide base sequence results in an even greater
diversity in TCR forms. This is called functional diversity.

5. As a result of combinatorial diversity and junctional diversity, each T-lymphocyte

is capable of generating a uniquely shaped T-cell receptor (TCR) capable of
reacting with complementary shaped peptides bound to MHC molecules.

6. As a result of T lymphocytes recognizing protein antigen epitopes during cell-

mediated immunity, many circulating T8 memory cells and T4 memory cells
develop that have anamnestic responses or memories.

7. Subsequent exposure to the same antigen results in faster and longer production
of cytotoxic T lymphocytes (CTL), and faster and longer production of T4 effector
lymphocytes.

8. When antigen encounters the immune system, the epitopes of antigen proteins
bound to MHC-I or MHC-II molecules will eventually react with naïve T4- and T8
lymphocytes with TCR and CD4 or CD8 molecules on their more or less matched
surfaces and this activate the T-lymphocytes. This process is known as clonal
selection.

9. Cytokines produced by effector T4-helper lymphocytes allow the now activated

T4 and T8 lymphocytes to multiply rapidly to produce large clones of thousands
of identical T4 and T8 lymphocytes. This is referred to as clonal expansion.