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Antigen Receptor Diversity

The human genome is presently estimated to contain 20–25 thousand genes. The number of T-cell receptors for antigen (TCRs) that we make is estimated at 2.5 x 107; the number of different kinds of antibody molecules (BCRs) is probably about the same.

Link to discussion of the structure of BCRs and TCRs.

How could 2.5 x 104 genes encode 2.5 x 107 different TCRs and the same number of different BCRs?

The answer: each receptor chain

is encoded by several different gene segments.

The genome contains a pool of gene segments for each type of chain. Random assortment of these segments makes the largest contribution to receptor diversity.

B cells

Gene segment usage for BCRs

For the heavy (H) chains of BCRs (antibodies), the gene segments are: All of these gene segments are clustered in a complex locus on chromosome 14.

During the differentiation of the B cell (and long before any encounter with an antigen), the DNA in this locus is cut and recombined to make an intact gene for the heavy chain. This gene can then be transcribed into pre-mRNA, which is then processed to form the mRNA that will be translated into the heavy (H) polypeptide chain.

V(D)J Joining

Some cases of severe combined immunodeficiency in humans (SCID) are caused by defects in V(D)J joining.
  • One version is caused by mutations in both copies of either RAG1 or RAG2.
  • Another is caused by mutations in a gene needed for nonhomologous end-joining. (No coding joint is formed even though a signal joint forms normally.)

If the 51 VH, 27 DH, and 6 JH gene segments were assembled randomly (they probably are not), that would provide a minimum of 8.3 x 103 different possible combinations.

But the possibilities of antibody V region diversity turn out to be greater than that. The recombination process is not precise.

Light chains

Once the H chain gene is assembled, transcribed, and translated, the resulting H chain can pair with an L chain that is itself the product of a similar recombination process occurring
Antibodies (BCRs)Gene SegmentsCombinations
5200 κ chains
4124 λ chains
JH67,650 H chains
Any H chain with any L chain (324)2.5 x 106

As the table shows, this lays the foundation for a potential B-cell repertoire of 2.5 x 106 different antibody V regions. But the true number is probably virtually limitless because of

Diversity comes at a price

The combining of V, D, and J gene segments coupled with the random incorporation of extra nucleotides (N regions) at the joints, creates enormous coding variability. It also creates a high risk (two times out of three) of introducing a frameshift so that the codons for the rest of the V region encode nonsense. Although many B cells are wasted, the odds are not quite as bad as they seem:

Somatic Hypermutation (SHM) and Antibody Diversity

The diversifying mechanisms described above take place before the B cell encounters antigen. After a B cell encounters antigen, it may begin mitosis, growing into a clone of cells synthesizing the same BCR (and, eventually, secreting antibodies with the same binding site). Point mutations can occur while this is going on. Some of these may generate a binding site with increased affinity for its epitope. These are favorable mutations, and the "subclone" in which they occur tends to be favored and may replace the ancestral clone. The result is affinity maturation — the production of antibodies of ever-increasing affinity for the antigen.

Class Switch Recombination (CSR)

As B cells grow into a clone in response to antigen, they may rearrange their DNA once again. For example, a B cell that has assembled a complete gene for the H chain of IgM (µ), may cut the gene on the 3´ side of the assembled V-region segments and move the assembly to the 5´ side of another of its CH gene segments. Now the cell begins to make a different class of antibody, such as IgG or IgA. But the antigen specificity of the antibody remains the same because the N-terminal of the H chain remains unchanged (as does the entire L chain).

Class switch recombination enables the body to produce antibodies with different effector functions; that is, different means of dealing with the same antigen.

The ability of a B cell to switch CH gene segments depends on its receiving help from helper T cells.

T Cells

Alpha/beta (αβ) T cells

The most abundant T cells in the blood express a receptor for antigen (TCR) that is a heterodimer of two chains designated alpha (α) and beta (β). Each of these is encoded by a gene assembled from V, D, J, and C gene segments. Like BCRs, there are multiple variants of these gene segments arranged in clusters:

T cell receptors (TCRs)Gene segmentsCombinations
502.5 x 103 alpha chains
2520 beta chains
Any alpha with any beta chain1.3 x 106

And like B cells, the greatest diversity in the receptors of αβ T cells occurs in the third complementarity determining region (CDR3) of the alpha and beta chains because of

However, T cells do not seem to use somatic mutation to increase receptor diversity. Actual measurements of the repertoire in humans reveals a figure of about 2.5 x 107.

Gamma/delta (γδ) T cells

The TCR repertoire of γδ T cells seems much smaller than that of their αβ cousins. The
Link to more information on γδ T cells.
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25 October 2011