T-Cell Receptors

The cell surface of a T lymphocyte contains receptormolecules
that with high specifity recognize
foreign antigens and cell surface molecules
of theMHCcomplex. The T-cell antigen receptor
(TCR) consists of a complex of several integral
plasma membrane proteins. Unlike B cells, T
cells recognize only fragments of foreign antigen
proteins. In addition, they bind physically
to the MHC complex of an antigen-presenting
cell. During maturation of the T cells in the thymus,
T-cell gene segments are rearranged in a
defined order by somatic recombination, similarly
to the formation of immunoglobulins.

T-cell receptor genes (TCR) of man

In the germ line, the genes for the ! chain of the
T-cell receptor consist of 75–100 variable segments
(V!), two D segments (D!1, D!2), two
joining segments (J!1, J!2), and two constant
segments (C!1, C!2). The genomic organization
of the genes for the ", #, and $ chains is similar.
During T-lymphocytematuration, different segments
are joined together by somatic recombination
as during B-cell maturation. In a given T
cell, only one of the two "-chain loci and only
one of the two !-chain loci become functionally
rearranged and expressed (allelic exclusion). As
in the rearrangement of immunoglobulin
genes, different mechanisms help produce diversity
of the T-cell receptor genes. The
genomic organization in humans and mice is
very similar. The !-chain genes are located on
chromosome 7 in humans and on chromosome
6 in mice. The "- and #-chain gene loci are located
on chromosome 14 in both humans and
mice. The $-chain genes lie on chromosome 7 in
humans and on chromosome 13 in mice.

T-cell receptor binding to antigens and MHC surface proteins

Unlike B cells, T cells recognize and react to foreign
protein antigens only when the antigens
are attached to the surface of other cells. Two
different classes of T lymphocytes recognize
different types of MHC gene products. T cells
with the ability to destroy other cells by cytolysis
(cytolytic T lymphocytes, CTLs, or “killer
cells”) recognize class I MHC molecules by
means of a coreceptor, CD8 (formerly T8). CD8 is
amembrane-bound glycoprotein of two dimers
(" and !),

........

e.g., CD3,
CD4, and CD8. CD4 is a coreceptor, a rod-shaped
single polypeptide with an extracellular part
consisting of four immunoglobulinlike
domains. The gp120 protein of the HIV virus reacts
with the second domain of CD4. A number
of accessorymembrane proteins of the CD3 system
participate in the specific binding between
TCR and MHC (TCR–CD3 complex). (Drawings
adapted from Abbas et al., 1997.)
The figures in B are highly schematic and do not
show the real three-dimensional structures.

Evolution of the Immunoglobulin Supergene Family

The many cell surface and soluble molecules of
the immune system that mediate different
functions such as recognition, binding, or adhesion
of specific molecules showmany structural
similarities. Some parts are found outside the
immune system. As a group, they constitute a
gene superfamily, derived from an ancestral
gene common to all members. The homologies
of the domains of their gene products and of
their gene sequences can be explained by evolutionary
origin from a common ancestral gene.
The Ig gene family members code for immunoglobulin
domains, usually of about 70–110
amino acids homologous with an Ig variable (V)
or constant (C) domain. Each Ig domain is
derived from conserved DNA sequences.

Basic structure of proteins of the immunoglobulin supergene family

The immunoglobulin molecules of the T-cell receptors
(TCR) and the class I and class II MHC
molecules (1) are basically similar. They consist
of variable Ig-like domains (V), constant Ig-like
domains (C), or primordial Ig-like domains (H).
Although their genes are located on different
chromosomes, the gene products form
functional complexes with each other. Others,
such as the V, D, and J gene segments of all antigen
receptors and their genes for the C domain
lie close together in gene clusters. In addition,
genes of the MHC loci and for the two CD8
chains lie together. The basic structures of accessory
molecules (2) such as CD2, CD3, CD4,
CD8, and thymosine 1 (Th-1) are relatively
simple. Other members of the Ig superfamily
(3) are the Fc receptor II (FcRII); polyimmunoglobulin
receptor (pIgR), which transports antibodies
through the membranes of epithelial
cells; NCAM (neural cell adhesion molecules);
and PDGFR (platelet-derived growth factor receptor)
(3).

Evolution of genes of the immunoglobulin supergene family

Distinct evolutionary relationships can be recognized
in the homology of genes for Ig-like
molecules. A precursor gene for a variant (V)
and a constant (C) region must have arisen by
duplication and subsequent diversification of a
gene for a primordial cell surface receptor. Such
a primordial gene could have looked like the
gene for thymosine (Thy-1) or poly-Ig receptor.
No somatic recombination occurs in these gene
families or in the genes of the MHC complex.
In contrast, the rearrangement of lymphocyte
germ-line genes by somatic recombination
during the maturation of B cells and T cells is
the basis for the formation of immunoglobulins,
T-cell receptors, and CD8. Somatic recombination
of the genes for antigen-binding molecules
was an enormous evolutionary advantage. Consequently,
this is found even in early vertebrates.

Hereditary and Acquired Immune Deficiencies

Numerous types of impairment of the immune
system exist, congenital (hereditary) and acquired.
All result in abnormal susceptibility to
infections, often associated with lymphoreticular
malignancies, and in some cases autoimmune
disease.

Examples of hereditary immune deficiency diseases

Severe combined immune deficiency (SCID) is a
heterogeneous group of genetic disorders due
to various defects in both B cell and T differentiation.
X-linked agammaglobulinemia type Bruton
(McKusick 300300) was the first hereditary immune
deficiency described, in 1952 by Ogden
Bruton. The first developmental step of B cell
differentiation from pre-B to mature B cell is
blocked by deficiency of Bruton tyrosine kinase
due to mutations in the BTK gene on the X chromosome
(Xq22). Other forms involve later steps
of differentiation (variable immune deficiency)
or isolated Ig isotype (subclass) deficiencies.
Several T cell immune deficiency diseases exist.
The most important is the DiGeorge syndrome
(McKusick 188400), characterized by a broad
spectrum of highly variable manifestations. The
underlying defect involves the third and fourth
brachial arch derivatives during embryonic
development. A deletion in chromosome region
22q11 is found in most patients, usually as a de
novo event. Other disorders involve T cell activation
and function of one or both major subsets
of T cells, CD4 or CD8.

Example of acquired immune deficiency: HIV-1 infection

The global epidemic of the acquired immune
deficiency syndrome (AIDS) due to the infection
with human immunodeficiency virus type 1
(HIV-1) poses a major public health problem of
unprecedented dimensions in modern times.
Although it was first noted in 1981 in restricted
populations, it now occurs in all populations at
all ages throughout the world (United Nations
Programme on HIV/AIDS at http://www.UNAIDS.
org/hivaidsinfo/documents-html). HIV-1
selectively infects T cells of the CD4 type. The
first step of infection is specific binding of the
extracellular domain of the viral transmembrane
glycoprotein gp120 to the CD4 receptor
(gp41 is the transmembrane protein). Two
chemokine receptors, CCR5 and CXR4, function
as major coreceptors (not shown in the figure).
Following virus genome uptake, a phase of viral
replication by reverse transcription into
double-stranded DNA occurs. Provirus DNA is
integrated into the cellular DNA by the virusencoded
integrase enzyme. As the infected cell
divides, the viral DNA (provirus) is also replicated.

HIV-1 provirus

The HIV-1 provirus can remain in the cell
without being transribed for a long period
(latent infection). Another phase of the HIV-1
life cycle involves transcription of viral DNA
(provirus) into viral RNA. The full-length RNA
transcripts are spliced and transported to the
cytoplasm. Here the viral RNA is translated into
viral proteins by cellular enzymes; the viral proteins
and RNA are then processed and assembled
into new virus particles (virus production).
These leave the cell as free infectious virions.
Usually the cell dies by lysis, but not always.
In this case low-level chronic virus production
may persist in infected individuals.

Origin of Tumors

Influence of Growth Factors on
Cell Division
Development, differentiation, and the maintenance
of vital functions require exact regulation
of the time and location of cell divisions.
Rapidly multiplying cells in embryonic tissues
must be controlled, just like those in stationary
phases in adult tissues. Rapid response to injury
or to foreign antigens requires controlled cell
division. Multicellular organisms have an extensive
repertoire of genetically regulated
mechanisms at their disposal for controlling
cell division and tissue proliferation. As a group,
they are referred to as growth factors. Every
growth factor has a specific cell surface receptor.
Binding to the receptor initiates (or in some
cases blocks) cell division. Most growth factors
regulate only certain types of cells and tissues.

Control of cell division by growth factors

Basically, cell division (mitosis) can be controlled
by stimulation or inhibition. In the absence
of stimulation or with active inhibition,
no mitosis occurs. Growth factors have an effect
not only on specific types of cells, but also on
defined phases of the cell cycle. The most
frequently controlled phase of the cell cycle is
the transition from G0 to G1. The growth factor
group includes growth factors for epidermal
cells (EGF), for nerve cells (NGF), for connective
tissue or mesenchymal cells (fibroblasts, FGF),
and for thrombus-forming cells in the inner lining
(endothelium) of blood vessels (PDGF).
Their stimulating effect may be opposed by an
antagonistic effect (e.g., TGF!, transforming
growth factor, or TNF, tumor necrosis factor).
The function of each growth factor is mediated
by a specific receptor.

Activation of a growth factor receptor

A growth factor receptor becomes activated by
specific extracellular binding to the growth factor.
The activated receptor in turn activates a
substrate protein.

PDGF-receptor kinases have an effect on numerous substrates

A receptor such as the PDGF (platlet-derived
growth factor) receptor can have an effect on
numerous substrates. Substrates of the PDGF
receptors include the Ras protein (see D), the
Src protein (the name is derived fromthe tumor,
a sarcoma, in which it was first found), phospholipase
C (a signal transmitter), and others.

Ras proteins as signal transmitters

The Ras proteins play a central role as signal
transmitters. They belong to the group of G proteins
(guanosine-residue-binding proteins with
signal-transmitting functions, see p. 266). The
binding of growth factor, e.g., PDGF, activates
the Ras protein by stimulating the conversion of
associated GDP (guanosine diphosphate) to GTP
(guanosine triphosphate) and triggering a short
time-limited signal that initiates cell division.
The signal is terminated by inactivation of Ras
by a GTPase-activating protein (GAP), which
converts GTP into GDP.Mutation of the Ras protein
or of GAP can remove the time limit of the
cell-stimulating signals and result in an active
condition with uncontrolled cell division. This
can lead to a tumor with uncontrolled growth
(malignancy). Several mutations have been defined
in the pertinent genes.

Tumor Suppressor Genes

Malignant tumors arise as a result of mutations
in three basic types of genes, DNA repair genes
(see p. 80 DNA repair), tumor suppressor genes,
and proto-oncogenes (see next plate). A single
mutation does not cause cancer. Rather several
mutations in different genes must accumulate
in one or several cells, which eventually lose
growth control in favor of aggressive growth
properties. Most mutations are somatic, i.e.,
limited to the neoplastic cells. A relatively small
subset ofmutations are present in the germline
(hereditary forms of cancer) and predispose the
individual to certain types of cancer.
Tumor suppressor genes encode proteins with
function in growth regulation or differentiation
pathways. Their name is derived from the observation
that one functional allele will
suppress tumor development even in the presence
of a mutation in the other allele (or its
loss). Thus, two mutational events are required
to release the growth-controlling function of a
tumor suppressor gene (see retinoblastoma,
p. 330). The two mutational events in a tumor
suppressor gene often become manifest in loss
of heterozygosity (LOH) in tumor cells (see B).
Tumor suppressor genes can be compared to
the brake of a car, cellular oncogenes

Tumor suppressor gene

In contrast to the cellular oncogenes, for which
a change in one allele will alter normal function,
both alleles of a tumor suppressor gene must
lose their function before a tumor develops. The
first event is usually a mutation by base exchange
or deletion. The second event, affecting
the other allele (allele 2), may also be a mutation,
but the loss of function more often appears
to be from loss of the chromosome after a faulty
cell division (mitotic nondisjunction) or other
mechanisms

Loss of heterozygosity in tumor cells

Usually, in about half of the individuals who are
heterozygous for DNA markers at the tumor
suppressor gene locus of interest, the loss of one
allele (event 2) can be demonstrated by Southern
blot analysis. In contrast to normal somatic
cells (blood), tumor cells contain only one allele
(loss of heterozygosity, LOH). The remaining allele
carries the mutation. Thus, the mutant allele
can be identified by demonstration of LOH.
LOH is useful in diagnosis as an indication of the
existence of a tumor suppressor gene.

Somatic and germinal mutation

The first mutation in a suppressor gene can
either be present in the zygote (germinal mutation,
i.e., germ cell mutation due to transmission
from an affected parent or due to new mutation)
or occur in a single cell of the corresponding
tissue (somatic mutation). Loss of
function of one allele (corresponding to event 1
in A) predisposes the cell to tumor development.

germinal mutation

With a germinal mutation, all cells are predisposed.
The tumor arises after loss of function
of the second allele. When somatic mutation
occurs in a single cell, loss of function of both
alleles rarely affects the same cell. But with a
germ cells mutation, loss of function of the second
allele is frequent, since all cells carry the
first mutation, i.e., are predisposed. With somatic
mutation, the tumor occurs sporadically
(is not hereditary) and arises unifocally from a
single cell. In the hereditary form resulting from
a germ cell mutation, several tumors may arise
from different cells (multifocal tumor). The predisposition
for the tumor in the hereditary form
shows autosomal dominant inheritance.