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.