ve classes of antibodies, therefore, contains up to millions
of unique immunoglobulins, each capable of combining with
only one speciﬁ c antigen (or, in some cases, several antigens
whose structures are very similar). The interaction between an
antigen binding site of an immunoglobulin and an antigen is
analogous to the lock-and-key interactions that apply gener-
ally to the binding of ligands by proteins.
One more point should be mentioned: B-cell receptors
can bind antigen whether the antigen is a molecule dissolved
in the extracellular ﬂ uid or is present on the surface of a for-
eign cell, such as a microbe, ﬂ
oating free in the ﬂ uids. In the
latter case, the B cell becomes linked to the foreign cell via the
bonds between the B-cell receptor and the surface antigen.
To summarize thus far, any given B cell or clone of iden-
tical B cells possesses unique immunoglobulin receptors—that
is, receptors with unique antigen binding sites. Thus, the body
arms itself with millions of small clones of different B cells in
order to ensure that speciﬁ c receptors exist for the vast num-
ber of different antigens the organism
its lifetime. The particular immunoglobulin that any given B
cell displays as a receptor on its plasma membrane (and that its
plasma cell progeny will secrete as antibodies) is determined
during the cell’s maturation in the bone marrow.
This raises a very interesting question: In the human
genome there are only about 200 genes that code for immu-
noglobulins. How, then, can the body produce immunoglob-
ulins having millions of different antigen binding sites, given
that each immunoglobulin requires coding by a distinct gene?
This diversity arises as the result of a genetic process unique to
developing lymphocytes because only these cells possess the
enzymes required to catalyze the process. The DNA in each
of the genes that code for immunoglobulin antigen binding
sites is cut into small segments, randomly rearranged along
the gene, and then rejoined to form new DNA molecules.
This cutting and rejoining varies from B cell to B cell, thus
resulting in great diversity of the genes coding for the immu-
noglobulins of all the B cells taken together.
T-cell receptors for antigens are two-chained proteins that,
like immunoglobulins, have speciﬁ c regions that differ from
one T-cell clone to another. However, T-cell receptors remain
embedded in the T-cell membrane and are not secreted like
immunoglobulins. As in B-cell development, multiple DNA
rearrangements occur during T-cell maturation, leading to mil-
lions of distinct T-cell clones—distinct in that the cells of any
given clone possess receptors of a single speciﬁ city. For T cells,
this maturation occurs during their residence in the thymus.
In addition to their general structural differences, the B-
and T-cell receptors differ in a much more important way:
T-cell receptor cannot combine with antigen unless the antigen is
rst complexed with certain of the body’s own plasma membrane
The T-cell receptor then combines with the entire
complex of antigen and body (self) protein.
The self plasma membrane proteins that must be com-
plexed with the antigen in order for T-cell recognition to occur
constitute a group of proteins coded for by genes found on a
single chromosome (chromosome 6) and known collectively
major histocompatibility complex (MHC).
proteins are therefore called
(in humans, also
known as the human leukocyte-associated antigens, or HLA
antigens). Because no two persons other than identical twins
have the same sets of MHC genes, no two individuals have the
same MHC proteins on the plasma membranes of their cells.
MHC proteins are, in essence, cellular “identity tags”—that
is, genetic markers of biological self.
The MHC proteins are often called “restriction elements”
because the ability of a T cell’s receptor to recognize an antigen
is restricted to situations in which the antigen is ﬁ rst complexed
with an MHC protein. There are two classes of MHC proteins:
I and II.
Class I MHC proteins
are found on the surface of
virtually all cells of a person’s body except erythrocytes.
II MHC proteins
are found only on the surface of macro-
phages, B cells, and dendritic cells.
Now for another important point: The different sub-
sets of T cells do not all have the same MHC requirements
). Cytotoxic T cells require antigen to be asso-
ciated with class I MHC proteins, whereas helper T cells
require class II MHC proteins. One reason for this difference
in requirements stems from the presence, as described earlier,
of CD4 proteins on the helper T cells and CD8 proteins on
the cytotoxic T cells; CD4 binds to class II MHC proteins,
whereas CD8 binds to class I MHC proteins.
How do antigens, which are foreign, end up on the sur-
face of the body’s own cells complexed with MHC proteins?
The answer is provided by the process known as
to which we now turn.
Antigen Presentation to T Cells
T cells can bind antigen only when the antigen appears on
the plasma membrane of a host cell complexed with the cell’s
MHC proteins. Cells bearing these complexes, therefore,
antigen-presenting cells (APCs).
Presentation to Helper T Cells
Helper T cells require class II MHC proteins to function. Only
macrophages, B cells, and dendritic cells express class II MHC
proteins and therefore can function as APCs for helper T cells.
MHC Restriction of the Lymphocyte
Do not interact with MHC proteins
Class II, found only on macrophages,
dendritic cells, and B cells
Class I, found on all nucleated cells of the
Interaction with MHC proteins not required