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15.4D: Antigen Receptors

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  • Both B cells and T cells have surface receptors for antigen. Each cell has thousands of receptors of a single specificity; that is, with a binding site for a particular epitope. T-cell receptors (TCRs) enable the cell to bind to and, if additional signals are present, to be activated by and respond to an epitope presented by another cell called the antigen-presenting cell or APC. B-cell receptors (BCRs) enable the cell to bind to and, if additional signals are present, to be activated by and respond to an epitope on molecules of a soluble antigen. The response ends with descendants of the B cell secreting vast numbers of a soluble form of its receptors. These are antibodies.


    Antibodies are glycoproteins. They are built of subunits containing two identical light chains (L chains), each containing about 200 amino acids and two identical heavy chains (H chains), which are at least twice as long as light chains. The first 100 or so amino acids at the N-terminal of both H and L chains vary greatly from antibody to antibody. T These are the variable (V) regions. Unless members of the same clone (and often not even then), no two B cells are likely to secrete antibodies with the same variable region. The amino acid sequence variability in the V regions is especially pronounced in 3 hypervariable regions. The tertiary structure of antibodies brings the 3 hypervariable regions of both the L and the H chains together. Together they construct the antigen binding site against which the epitope fits. For this reason, the hypervariable regions are also called complementarity determining regions (CDRs). Only a few different amino acid sequences are found in the C-terminals of H and L chains. These are the constant (C) regions.

    Humans make two different kinds of C regions for their L chains producing kappa (κ) L chains and lambda (λ) L chains. They also make five different kinds of C regions for their H chains producing:

    • mu (µ) chains (the H chain of IgM antibodies)
    • gamma (γ) chains (IgG)
    • alpha (α) chains (IgA)
    • delta (δ) chains (IgD)
    • epsilon (ε) chains (IgE)

    Each of these 5 kinds of H chains seems to have no particular preference for pairing with lambda or kappa L chains.

    Figure IgG molecule

    This image represents the polypeptide chain structure of a molecule of IgG. The numbers indicate the number of amino acids (counting from the amino terminal ("N"). In the actual molecule, the chains are folded to that each cysteine is brought close to the partner with which it forms a disulfide (S–S) bridge.

    Figure Tertiary structure of L chain courtesy of Dr. D. R. Davies

    The images above() represent the folded (tertiary) structure of an entire L chain (right side with thin connecting lines) and the V region plus the first third of the C region of a heavy chain (left side; darker lines). Each circle represents the location in 3D space of an alpha carbon. The filled circles at the top are amino acids in the hypervariable or complementary determining regions (CDRs); they form the site that binds the antigen.

    Antibody molecules have two functions to perform:

    • recognize and bind to an epitope on an antigen
    • trigger a useful response to the antigen

    The division of labor is:

    • V regions are responsible for epitope recognition.
    • C regions are responsible for triggering a useful response

    So, V regions finger the culprit; the C regions take action.

    If an antibody's H chains (see IgG above), are cut at its hinge region on the N-terminal side of the disulfide bonds holding the H chains together, 3 fragments are produced:

    • 2 Fab fragments ("fragment antigen-binding") and
    • 1 Fc fragment ("fragment crystalline" — because the uniformity of this region allows crystals to form while the great diversity of V regions prevents them from forming).

    Why 5 kinds of heavy chains? To provide for different effector functions.

    The 5 classes of antibodies
    Class H chain L chain Subunits mg/ml Notes
    IgG gamma kappa or lambda H2L2 6–13 transferred across placenta; four subclasses: IgG1-4 in humans
    IgM mu kappa or lambda (H2L2)5 0.5–3 first antibodies to appear after immunization
    IgA alpha kappa or lambda (H2L2)2 0.6–3 much higher concentrations in secretions; two subclasses
    IgD delta kappa or lambda H2L2 <0.14 function uncertain
    IgE epsilon kappa or lambda H2L2 <0.0004 binds to basophils and mast cells sensitizing them for certain allergic reactions

    "mg/ml" gives the concentration normally found in human serum. The subclasses of IgG and IgA are encoded by different C-region gene segments.

    If an antibody-secreting cell becomes cancerous, it will grow into a clone secreting its single class of molecule. The disease is called multiple myeloma.

    T-Cell Receptors for Antigen (TCRs)

    alpha/beta (αβ) T cells

    The antigen receptor on most T cells is made up of two transmembrane polypeptides designated alpha and beta (thus forming a heterodimer).

    Like antibodies each has an N-terminal variable region with 3 hypervariable or complementary determining regions (CDRs). The CDRs of the two chains cooperate to form a single binding site for the epitope. The epitope seen by T cells consists of an antigenic peptide inserted into a groove formed by a major histocompatibility complex (MHC) molecule. Typically the two super-variable CDR3s bind to the peptide while the less variable CDR1s and CDR2s bind to the MHC molecule.

    gamma/delta (γδ) T cells

    A small percentage of the T cells in the blood use a TCR consisting of a heterodimer of two other types of transmembrane polypeptides: gamma and delta. The function of this subset of T cells is still a mystery.

    Antigen Receptor Genes

    Each chain of a BCR or TCR is encoded by a gene that is assembled from separate gene segments during the differentiation of the cell. The resulting gene is transcribed into a mRNA to be translated into one chain of the receptor. The number of gene segments from which the variable regions are constructed is sufficiently large that both B cells and T cells can generate more than 107 different antigen-binding sites. There is probably no epitope that could exist for which BCRs and TCRs able to bind it are not built.