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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. [View]
- 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
  - lambda (λ) L chains
- 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

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 or complementary determining regions (CDRs); 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" (about 46 cm) 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.

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. See how IgG, IgM, and IgA molecules appear in the serum of these patients.

Bispecific Antibodies

The antibodies produced by normal B cells have two identical Fab fragments with identical antigen-binding specificities. However, in the laboratory it is possible through cell fusion and genetic engineering techniques to make B cell clones that generate antibodies with differing specificities; that is, one Fab that binds a particular epitope, with the other Fab binding a different epitope.

Example: mosunetuzumab. The antibodies secreted by this B-cell clone have

one arm that binds CD20, a protein found on the surface of myeloma cells and
the second arm that binds CD3, a cell surface protein on T cells.

Presumably, mosunetuzumab binds and activates the T cell while linking it to the malignant myeloma cell which it can then destroy (e.g., by releasing granules of granzyme B and perforin).

Mosunetuzumab is one of several bispecific antibodies that have produced substantial remissions in patients with multiple myeloma and patients with B-cell lymphomas.

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 [View]. Typically
- the two super-variable CDR3s bind to the peptide while
- the less variable CDR1s and CDR2s bind to the MHC molecule.

Links to more on αβ T cells:

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. [More]

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.

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

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26 January 2023