7. Organization and rearrangement of the antigen receptor genes

Page created on March 7, 2018. Last updated on November 19, 2018 at 17:16

Organization and recombination of the immunoglobulin genes, VDJ recombination

For the adaptive immune system to work, each individual B-cell has to create different antibodies that can bind to different antigens, so that when a pathogen invades, at least one antibody can bind to one of the pathogen’s antigens. Because antibodies are just protein transcribed from DNA, the immunoglobulin-coding gene in each B-cell must be slightly different. This is done by recombination of the DNA, which deletes certain elements in the gene to make sure one B-cell gets a unique copy.

The organization of the Ig heavy chain gene. The red are called «variable» segments, the green «diversity», the yellow «joining» and the blue «constant». The segments are very underrepresented. There are actually 65 V segments, 27 D and 6 J.

Starting with the heavy chain, it’s gene looks like this. Each box is a genetic segment that makes up the gene. The red segments are called “variable” (V), the green are called “diversity” (D), the yellow are called “joining” (J), and the blue are constant and are not modified.

During B-cell development, this gene (and the gene for the light chain, which we will see later) will be reorganized. When finished, the gene will only contain only one of each type of segment. So, the B-cell will cut out all but one V segment, all but one D segment, and all but one J segment, and put the three (randomly chosen) remaining segments together. These VDJ segments will code for the variable domain on the heavy chain, while the C segments will code for the constant domains (there is one C segment for each heavy chain isotype). Because there are 65 V segments, 27 D segments and 6 J segments to choose from, there are very many possibilities for recombination, roughly 3×1011. Each V, D and J combination will yield an B cell that can produce antibodies that can recognize different epitopes. After recombination, the gene might for example look like this:

After recombination, only one V, one D, and one J remain. The C are untouched.

Because the light-chain can be either κ or λ, there are two genes encoding for it. Their genes are very similar in build-up to the gene for the heavy chain, except the light chains don’t have D segments, just V, J and C.

There are several proteins needed for this recombination. Recombination-activating gene 1 & 2 (RAG1 & RAG2), and terminal deoxynucleotide transferase (TdT) are essential. TdT fixes double stranded DNA damage during recombination.

Recall the structure of the variable domain of antibodies. Each variable domain contains three CDR-regions, CDR1, CDR2 and CDR3. The CDR1 and CDR2 are mostly built up of the V gene segment, while CDR3 is built up of V, D and J. This causes CDR3 to be the most variable of the CDR.

Another principle called allelic exclusion makes sure that the B-cell only expresses and uses one of the two alleles (gene copies) for immunoglobulin it has in its genome. We have two copies of every gene in our genome, and both can undergo VDJ recombination. The way the B-cell decides which of the alleles to express is like this: The B-cell first performs VDJ recombination on one of the alleles. If this recombination succeeds, the other allele is deactivated. If it fails, the B-cell will perform VDJ recombination of the other allele. If this should also fail, the B-cell will die, as it could not perform VDJ recombination of any of the alleles and therefore has no functioning heavy chain gene. Allelic exclusion ensures that all the heavy chains the B-cell produces are identical.

Another principle called isotype exclusion means that each B-cell produces either κ or λ light chains, not both. The B-cell chooses one of them to express and then deactivates the gene for the other to ensure that all light chains the B-cell produces are the same.

Organization and recombination of the T-cell receptor genes

Recall the structure of the T-cell receptor. It has one α-chain and one β-chain. The genes for the two chains are separated, but similar to the genes for the immunoglobulins. The gene for the TCR β chain contains V, D, J and C gene segments, like the Ig heavy chain, while the gene for the TCR α chain contains only V, J and C segments, like the Ig light chain. Recombination happens just like for Ig’s.

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