Antigen Receptors

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.

Discussion of antigen presentation to B cells and T cells

Antibodies

are glycoproteins
are built of subunits containing
- two identical light chains (L chains), each containing about 200 amino acids
- 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
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
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 L chains
  - lambda L chains
- five different kinds of C regions for their H chains producing
  - mu chains (the H chain of IgM antibodies)
  - gamma chains (IgG)
  - alpha chains (IgA)
  - delta chains (IgD)
  - epsilon chains (IgE)
- each of these 5 kinds of H chains seems to have no particular preference for pairing with lambda or kappa L chains

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.

The images below (courtesy of Dr. D. R. Davies) 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 regions; they form the site that binds the antigen.

Do try to fuse these two images into a stereoscopic (3D) view. I find that it works best when my eyes are about 18" from the screen and I try to relax so that my eyes are directed at a point behind the screen.

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.

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	13	transferred across placenta
IgM	mu	kappa or lambda	(H₂L₂)₅	0.5-2.5	first antibodies to appear after immunization
IgA	alpha	kappa or lambda	(H₂L₂)₂	0.5-3	much higher concentrations in secretions
IgD	delta	kappa or lambda	H₂L₂	0.03	function uncertain
IgE	epsilon	kappa or lambda	H₂L₂	0.0003	binds to basophils and mast cells sensitizing them for certain allergic reactions

"mg/ml" gives the concentration normally found in human serum.
Note also that humans actually make four slightly different versions of IgG (and two of IgA); in both cases, encoded by different C-region gene segments.

T-Cell Receptors for Antigen (TCRs)

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
the variable regions of the two chains cooperate to form a single binding site for the epitope

gamma/delta 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

All the antibody Heavy chains, lambda L chains, kappa L chains, T cell alpha, beta, gamma, and delta chains are encoded by genes that are assembled from separate gene segments during the differentiation of the cell. The result is a single gene that 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 as many as 10¹⁰ different antigen-binding sites. There is probably no epitope that could exist for which BCRs and TCRs able to bind it are not be built.

The mechanisms by which B cells and T cells generate receptors of such extraordinary diversity.

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19 May 1999