The genes encoding the four subunits (α, β, γ, δ) of the T-cell receptor (TCR) are located at different chromosomal positions in the human genome:
- α chain – Chromosome 14 (14q11.2)
- β chain – Chromosome 7 (7q34)
- γ chain – Chromosome 7 (7p14)
- δ chain – Chromosome 14 (14q11.2)
Our First Encounter with Allelic Exclusion
The genetic reason why a single T cell cannot simultaneously express both the αβ and γδ TCR subunits lies in the mechanism of allelic exclusion during TCR gene rearrangement.
During T cell development in the thymus, the TCRα locus on chromosome 14 and the TCRβ locus on chromosome 7 undergo V(D)J recombination in an attempt to generate a functional αβ TCR.
If a productive αβ TCR is successfully assembled, the cell downregulates the accessibility of the TCRγ and TCRδ loci through epigenetic modifications like DNA methylation. This prevents any further rearrangement at those loci.
Conversely, if the initial attempts at αβ TCR rearrangement fail, the TCRγ and TCRδ loci are kept open and accessible for rearrangement instead, allowing production of a γδ TCR receptor.
This allelic exclusion mechanism ensures that a T cell only expresses one type of TCR, either αβ or γδ, but not both simultaneously. Co-expression could lead to mispairing of the TCR subunits.
The genomic co-localization of the TCRα and TCRδ loci on chromosome 14 likely facilitates this allelic exclusion mechanism through coordinated epigenetic regulation of the two loci during development.
So in essence, while αβ and γδ T cells develop through the same overall pathway, the allelic exclusion imposed on these divergent TCR loci ensures each mature T cell expresses just one specific heterodimeric TCR, never a hybrid combination of different subunits.
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Source: Claude 3 Sonnet response prompted and edited by Joel Graff.
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