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4

Antigen Receptor Genes, Gene Products,

and Coreceptors

Harry W. Schroeder, Jr., John B. Imboden, Raul M. Torres

In 1890, von Behring and Kitasato reported the existence of an companion α chain led to the realization that there were two
agent in blood that could neutralize the diphtheria toxin. The mutually exclusive forms of TCR, αβ and γδ.
following year, glancing references were made to “Antikörper”
in studies describing the ability of the agent to discriminate PARATOPES AND EPITOPES
between two immune bodies, or substances. The term antigen
is a shortened form of “Antisomatogen + Immunkörperbildner,” Igs and TCRs both belong to the eponymous Ig superfamily
1
or the substance that induces the production of an antibody (IgSF). The study of antibodies precedes that of TCR by decades;
(Chapter 6). Thus the definition of antibody and antigen represent hence much of what we know is based on knowledge first gleaned
a classic tautology. from the study of Igs.
In 1939, Tiselius and Kabat used electrophoresis to separate Ig–antigen interactions typically take place among the paratope,
immunized serum into albumin, α-globulin, β-globulin, and the site on the Ig at which the antigen binds, and the epitope,
γ-globulin fractions. Absorption of the serum against the antigen which is the site on the antigen that is bound. Thus lymphocyte
depleted the γ-globulin fraction; yielding the terms gammaglobu- antigen receptors do not recognize antigens, but they recognize
lin, immunoglobulin (Ig), and IgG. Subsequently, “sizing” columns the epitopes borne on those antigens. This makes it possible for
were used to separate Igs into those that were “heavy” (pentameric the cell to discriminate between two closely related antigens,
IgM), “regular” (IgA, IgE, IgD, IgG, monomeric IgM), and “light” each of which can be viewed as a collection of epitopes. It also
(light-chain dimers), culminating with the discovery of the last permits the same receptor to bind divergent antigens that share
major class of immunoglobulin, IgE, in 1966. equivalent or similar epitopes, a phenomenon referred to as
In 1949, Porter used papain to digest IgG molecules into two cross-reactivity.
types of fragments, termed Fab (fragment antigen-binding) and Although both Igs and TCRs can recognize the same antigen,
Fc (fragment crystallizable). The constancy of the Fc fragment they do so in markedly different ways. Igs tend to recognize
permitted its crystallization and thus the elucidation of its intact antigens in soluble form, and thus preferentially identify
sequence and structure. The variability of the Fab fragment surface epitopes that are often composed of conformational
precluded analysis until Bence-Jones myeloma proteins were structures noncontiguous in the antigen’s primary sequence.
identified as clonal, isolated light chains. In contrast, TCRs recognize fragments of antigens, both
In 1976, Hozumi and Tonegawa demonstrated that the variable surface and internal, that have been processed by a separate
portion of κ chains was the product of the rearrangement of antigen-presenting cell (APC) and then bound to a major
variable (V) and joining (J) gene segments. In 1982, Alt and histocompatibility complex (MHC) class I or class II molecule
Baltimore reported that terminal deoxynucleotidyl transferase (Chapters 5, 6).
(TdT) could be used to introduce non-germline–encoded
sequence between rearranging V, D (diversity), and J gene seg- THE BCR AND TCR ANTIGEN
ments, potentially freeing the preimmune heavy-chain repertoire RECOGNITION COMPLEX
from germline constraints. In 1984, Weigert et al. determined
that during affinity maturation, variable domains could undergo Although the ability of the surface antigen receptor to recognize
-3
mutation at a rate of 10 per base pair (bp), per generation. antigen was appreciated early on, the mechanism by which the
These discoveries clarified how lymphocytes could generate an membrane-bound receptor relayed this antigen recognition
astronomically diverse antigen receptor repertoire from a handful event into the cell interior was not understood, since both B-cell
of gene elements. receptor (BCR) and TCR cytoplasmic domains are exceptionally
In 1982, Allison et al. raised antisera against a cell surface short. This conundrum was solved when it was shown that BCR
molecule that could uniquely identify individual T-cell clones. and TCR each associate noncovalently with signal transduction
A year later, Kappler and a consortium of colleagues demonstrated complexes: heterodimeric Igα:Igβ (also known as CD79a:CD79b,
that these surface molecules were heterodimers composed of respectively) for B cells and multimeric CD3 for T cells. Loss
variable and constant region domains, just like Igs. Subsequently, of function mutations in either of these complexes leads to
Davis and Mak independently cloned the β chain of the T-cell cell death, which becomes clinically manifest as hypogam-
receptor (TCR). Initial confusion regarding the identity of the maglobulinemia in the case of B cells (Chapter 34), or severe

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