Cells of Adaptive Immunity
The
principal cells of the adaptive immune system are the lymphocytes, APCs, and
effector cells.
Lymphocytes
Lymphocytes
make up approximately 36% of the total white cell count and are the primary
cells of the adaptive immune response. They arise from the lymphoid stem cell
line in the bone marrow and differentiate into two distinct but inter-related
cell types: the B lymphocytes and T lymphocytes. B lymphocytes are responsible
for forming the antibodies that provide humoral immunity, whereas T lymphocytes
provide cell-mediated immunity. T and B lymphocytes are unique in that they are
the only cells in the body capable of recognizing specific antigens present on
the surfaces of microbial agents and other pathogens. As a result, adaptive
immune processes are organism specific and possess the capacity for memory.
The
recognition of specific surface antigens by lymphocytes is made possible
because of the presence of specific receptors or antibodies on the surface of B
and T lymphocytes. Scientists have been able to identify these specific
proteins and correlate them with a specific cellular function. This has lead to
the development of a classification system for these surface molecules known as
the “cluster of differentiation” (CD). The nomenclature for the surface
proteins utilizes the letters “CD” followed by a number that specifies the
surface proteins that define a particular cell type or stage of cell
differentiation and are recognized by a cluster or group of antibodies. The
utilization of this nomenclature has spread to other immune cells and cytokines
all of which contribute to the acquired immune response.
Leukocytes
involved in the innate immune response, such as macrophages and DCs, also play
a key role in adaptive immunity because they function as APCs. They are capable
of processing complex antigens into epitopes, which are then displayed on their
cell membranes in order to activate the appropriate lymphocytes. Functionally,
there are two types of immune cells: regulatory cells and effector cells. The regulatory
cells assist in orchestrating and controlling the immune response, while
effector cells carry out the elimination of the antigen (microbial, non microbial, or toxin). In the body, helper T
lymphocytes activate other lymphocytes and phagocytes, while regulatory T cells
keep these cells in check so that an exaggerated immune response does not
occur. Cytotoxic T lymphocytes, macrophages, and other leukocytes function as
effector cells in different immune responses.
While T
and B lymphocytes are generated from lymphoid stem cells in the bone marrow,
they do not stay there to mature.
Undifferentiated,
immature lymphocytes migrate to lymphoid tissues,
where they develop into distinct types of mature lymphocytes (Fig. 13.5). The T
lymphocytes first migrate to the thymus gland where they divide rapidly and
develop extensive diversity in their ability to react against different
antigens. Each T lymphocyte develops specificity against a specific antigen.
Once this differentiation occurs, the lymphocytes leave the thymus gland and
migrate via the bloodstream to peripheral lymphoid tissue. At this time, they
have been preprogrammed not to attack the body’s own issues. Unfortunately, in
many autoimmune diseases it is believed that this process goes astray. The B
lymphocytes mature primarily in the bone marrow and are essential for
humoral, or antibody-mediated, immunity. Unlike the T
lymphocytes, where the entire cell is involved in the immune response, B
lymphocytes secrete antibodies, which then act as the reactive agent in the
immune process. Therefore, the lymphocytes are distinguished by their function
and response to antigen, their cell membrane molecules and receptors, their
types of secreted proteins, and their tissue location. High concentrations of
mature lymphocytes are found in the lymph tissue throughout the body including
the lymph nodes, spleen, skin, and mucosal tissues.
T and B
lymphocytes possess all of the processes necessary for the adaptive immune
response specificity, diversity, memory, and self–nonself recognition. When
antigens come in contact with the lymphocytes in the lymphoid tissues of the body, specific T cells become activated and specific
B cells are stimulated to
produce antibodies. Once the first encounter occurs, these cells can exactly
recognize a particular microorganism or foreign molecule because each
lymphocyte is capable of targeting a specific antigen and differentiating the
invader from self or from other substances that may be similar to it.
Cell-mediated and humoral immunity is capable of responding to millions of
antigens each day because there is an enormous variety of lymphocytes that have
been programmed and selected during cellular development. Once the invading
sub- stance or organism has been removed from the body, the lymphocytes
“remember” the presenting antigen and can respond rapidly during the next
encounter. These lymphocytes are called “memory” T and B lymphocytes. They
remain in the body for a longer period of time
than their predecessors and as a result can respond
more rapidly on repeat exposure. The immune system usually can respond to
commonly encountered microorganisms so efficiently that we are unaware of the
response.
B and T
lymphocyte activation is triggered by
antigen presentation to unique surface receptors (Fig. 13.6). The
antigen receptor present on the B lymphocyte consists of membrane-bound Ig
molecules that can bind a specific epitope. However, in order for B lymphocytes
to produce antibodies, they require the help of specific T lymphocytes, called helper
T cells. While the B lymphocytes bind to one determinant (or hapten) on an
antigen molecule, the antigen-specific helper T cell recognizes and binds to
another determinant known as the “carrier.” The carrier is an APC, which has
previously picked up the specified
antigen. This interaction (B cell–T cell–APC) is
restricted by the presence of cellular products genetically encoded by a
self-recognition protein, called a major histocom-patibility complex (MHC)
molecule. This allows the lymphocyte to differentiate between self and foreign
peptides.
Once the
B and T lymphocytes are activated and amplified by cytokines released as part
of the innate response, the lymphocytes divide several times to form
populations or clones of cells that continue to differentiate into several
types of effector and memory cells. In the adaptive immune response, the
effector cells destroy the antigens and the memory cells retain the ability to
target antigen during future encounters.
Major
Histocompatibility Complex Molecules
In order
for the adaptive immune response to function properly, it must be able to
discriminate between molecules that are native to the body and those that are
foreign or harmful to the body. The T lymphocytes are designed to respond to a
limitless number of antigens, but at the same time they need to be able to
ignore self-antigens expressed on tissues. The MHC molecules enable the
lymphocytes to do just this. The MHC is a large cluster of genes located on the
short arm of chromosome 6. The complex occupies approximately 4 million base
pairs and contains 128 different genes, only some of which play a role in the
immune response. The MHC genes are divided in three classes: I, II, and III,
based upon their underlying function
(Fig. 13.7).
The class
I and II MHC genes are responsible for encoding human leukocyte antigens
(HLAs), which are proteins found on cell surfaces and define the individual’s
tissue type. These molecules are present on the cell surface glycoproteins that
form the basis for human tissue typing. Each individual has a unique collection
of MHC proteins representing a unique set of polymorphisms. MHC polymorphisms
affect immune responses as well as susceptibility to a number of diseases.
Because of the number of MHC genes and the possibility of several alleles for
each gene, it is almost impossible for any two individuals to have an identical
MHC profile.
The class
I and II MHC genes also encode proteins that play an important role in antigen
presentation. Protein fragments from inside the cell are displayed by MHC
complex on the cell surface, allowing the immune system to differentiate
between the body’s own tissues and foreign substances. Cells, which present
unfamiliar peptide fragments on the cell surface, are attacked and destroyed by
the B and T lymphocytes. Class III MHC genes encode for many of the components
of the complement system and play an important role in the innate immune
process.
The MHC-I
complexes contain a groove that accommodates a peptide fragment. T-cytotoxic
cells can only become activated if they are presented with a foreign antigen
peptide. MHC-1 complexes may present degraded viral protein fragments from
infected cells. Class II MHC (MHC-II) molecules are found only on
phagocytic APCs, immune cells that engulf foreign particles including bacteria
and other microbes. This includes the macrophages, DCs, and B lymphocytes,
which communicate with the antigen receptor and CD4 molecule on T-helper
lymphocytes.
Like
class I MHC proteins, class II MHC proteins have a groove or cleft that binds a
fragment of antigen. However, these bind fragments from pathogens that have
been engulfed and digested during the process of phagocytosis. The engulfed
pathogen is degraded into free peptide fragments within cytoplasmic vesicles
and then complexed with the MHC-II molecules on the surface of the cells.
T-helper cells recognize these complexes on the surface of APCs and become
activated.
The first
human MHC proteins discovered are called human leukocyte antigens (HLAs)
and are so named because they were identified on the surface of white blood
cells. HLAs are the major target involved in organ transplant rejection and as
a result are the focus of a great deal of research in immunology. Recent
analysis of the genes for the HLA molecules has allowed for better
understanding of the proteins involved in this response. The classic human
MHC-I molecules are divided into types called HLA-A, HLA-B, and HLA-C, and the
MHC-II molecules are identified as HLA-DR, HLA-DP, and HLA-DQ (Table 13.3).
Multiple alleles or alternative genes can occupy each of the gene loci that
encode for HLA molecules. More than 350 possible alleles for the A locus, 650
alleles for the B locus, and 180 alleles for the C locus have been identified.
These genes and their expressed MHC molecules are designated
by a letter
and numbers (i.e., HLA-B27).
HLA genes are inherited as a unit, called a haplotype, because the class I and II MHC genes are closely
linked on one chromosome. Since each person inherits one chromosome from each
parent, each person has two HLA haplotypes. Tissue typing in forensics and
organ transplantation involves the identification of these haplotypes. In organ
or tissue transplantation, the closer the matching of HLA types, the greater is
the probability of identical antigens and the lower the chance of rejection.
However, not all people that develop organ rejection after transplantation
develop anti-HLA antibodies. Non-HLA target antigens exist including the MHC
class I chain-related antigens A (MICA). These antigens are expressed on
epithelial cells, monocytes, fibroblasts, and endothelial cells. Therefore,
donor-specific antibodies are not detected prior to organ tissue typing prior
to transplantation because they are not expressed on the leukocytes tested.
Antigen-Presenting
Cells
During
the adaptive immune response, activation of a T lymphocyte requires the
recognition of a foreign peptide (antigen) bound to a self-MHC molecule. This
process requires that stimulatory signals be delivered simultaneously to the T
lymphocyte by another specialized cell known as an antigen- presenting cell
(APC). Therefore, APCs play a key role in bridging the innate and adaptive
immune systems through cytokine-driven up-regulation of MHC-II molecules. Cells
that function as APCs must be able to express both classes of MHC molecules and
include DCs, monocytes, macrophages, and B lymphocytes residing in lymphoid follicles.
Under certain conditions, endothelial cells are also able to function as APCs.
APCs have been shown to play a key role in the development of autoimmune
diseases and atherosclerosis. Activated T lymphocytes appear to be
proatherogenic, and in experimental models, APC and T-cell deficiency have been
associated with up to an 80% reduction in atherosclerosis.
Macrophages
function as a principal APC. They are key cells of the mononuclear phagocytic
system and engulf and digest microbes and other foreign substances that gain
access to the body. Since macrophages arise from monocytes in the blood, they
can move freely throughout the body to the appropriate site of action. Tissue
macrophages are scattered in connective tissue or clustered in organs such as
the lung (i.e., alveolar macrophages), liver (i.e., Kupffer
cells), spleen, lymph nodes, peritoneum,
central nervous system (i.e., microglial cells),
and other areas. Macrophages are activated during the innate immune response
where they engulf and break down complex antigens into peptide fragments. These
fragments can then be associated with MHC-II molecules for presentation to
cells of the “cell-mediated” response so that self–nonself recognition and
activation of the immune response can occur.
DCs are
also responsible for presenting processed antigen to activated T lymphocytes.
The starlike structure of the DCs provides an extensive surface area rich in
MHC-II molecules and other non-HLA molecules important for initiation of
adaptive immunity. DCs are found throughout the body in tissues where antigen
enters the body and in the peripheral lymphoid tissues. Both DCs and
macrophages are capable of “specialization” depending upon their location in
the body. For example, Langerhans cells are specialized DCs in the skin,
whereas follicular DCs are found in the lymph nodes. Langerhans cells transport
antigens found on the skin to nearby lymph nodes for destruction. They are also
involved in the development of cell-mediated immune reactions such as allergic
type IV contact dermatitis. Finally, DCs are found in the mucosal lining of the
bowel and have been implicated in the development of inflammatory bowel
diseases such as Crohn disease and ulcerative colitis, where they present antigens
to the B and T lymphocytes through the production of proinflammatory cytokines.
