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66 Part one Principles of Immune Response

TCR αδ locus
Vδ

V α (n = 42) Dδ Jδ Jα
Vδ4 Vδ6 Vα Vδ1 Vα Vδ5/Vα17.1 δ rec Vδ2 Dδ1 Dδ2 Dδ3 Jδ1 Jδ2 Jδ3 Cδ Vδ3 TEA ΨJα Cα
5’ 3’
Chr. 14q11-12 δ enhancer α enhancer

TCR β locus
Vβ (n = 47) Jβ1 Jβ2 Vβ
Dδ1 Cβ1 Dδ2 Cβ2
Chr. 7q35 5’ 3’
β enhancer

TCR γ locus
* Exon 2 encodes cysteine
Vγ1 Vγ2 Jγ1 Jγ2
Cγ1* Cγ2
Chr. 7q14-15 5’ 3’
γ enhancer
FIG 4.9 Chromosomal Organization of the T-Cell Receptor (TCR) αδ, β, and γ Gene Clusters.
Typical numbers of functional gene segments are shown. These maps are not drawn to scale.

with rearrangement occurring at the allele that replicates early;
The TCR γ Chain Locus localization of the active allele to a more central, euchromatic
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The γ locus is located at chromosome 7p14-15. There are 4–6 region of the nucleus; and DNA demethylation of the active allele.
functional Vγ region segments intermixed with pseudogenes, Once a functional V domain has been generated, rearrangement
no Dγ, and two J clusters with a total of 5 J segments. Each J terminates with the expression of a membrane-bound Ig or
cluster is 5’ to its C region (see Fig. 4.9). The Vγ segments have TCR product capable of transducing a signal. In preB cells, a
been divided into six families, although only Vγ1 (nine members, functional µ H chain associates with the surrogate light chain
five of them functional) and Vγ2 (one member) encode functional to form the preBCR. Similarly, in developing T cell progenitors,
proteins. The number of Cγ gene exons varies: Cγ1 has three, a productive TCR β chain associates with preTα to form the
whereas there are two alleles of Cγ2 that have four and five, preTCR. These preliminary antigen receptors signal to shut
respectively. The first Cγ exon encodes most of the extracellular down RAG expression, promote cell division, and limit the
portion of this region. The last Cγ exon encodes the intracyto- accessibility of the IgH and TCRβ loci to further rearrangement
plasmic portion of the molecule. The middle exon(s) (one for while promoting the accessibility of the IgL and TCRα loci,
Cγ1, two or three for Cγ2) encode the connecting piece, which respectively.
does (Cγ1), or does not (Cγ2), include a cysteine. Since this In preB cells, the κ locus is typically the first to rearrange,
cysteine can form a disulfide bond with another cysteine in the with λ rearrangement primarily occurring in cells that have failed
δ chain, TCRs using Cγ1 contain a covalently linked γ–δ pair, to produce a proper κ chain. Surface expression of an acceptable
whereas TCRs using Cγ2 do not. membrane-bound IgM BCR invokes the mechanism of allelic
The nomenclature of the human γ locus differs among labo- exclusion among the L chain loci, termed isotypic exclusion, and
ratories and reports and is extensively cross-referenced on the promotes further maturation of the B cell.
+
+
IMGT website (http://www.imgt.org). Productive TCRα rearrangement in CD4 CD8 T-cell progeni-
tors allows the expression of a functional TCR αβ heterodimer
Allelic Exclusion (Chapter 9). Unlike IgH and TCRβ, TCRα does not undergo
Because of the inherently imprecise nature of coding joints, only allelic exclusion at the level of gene rearrangement. Instead, in
one in three V(D)J Ig or TCR rearrangements will be in-frame cells that express two functional TCRα alleles, one of the two
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and capable of creating a functional protein. Theoretically, one alleles tends to preferentially pair with the one functional TCRβ
in nine cells might be expected to express two different Ig or chain. This is termed phenotypic allelic exclusion.
TCR chains. However, almost all B cells express the functional Allelic exclusion can be overcome by selection pressures.
products of only one IgH allele and one IgL allele, and mature Developing lymphocytes that express self-reactive antigen recep-
αβ T cells express only one functional TCRβ gene. The process tors can downregulate IgH or TCR expression and reactivate
of limiting the number of receptors expressed by an individual gene rearrangement to replace one of the two offending chains.
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cell is known as allelic exclusion. 41 This process, termed receptor editing, occurs most often in the
The mechanisms that ensure monoallelic expression are IgL or TCRα loci, whose gene structures lend themselves to
most commonly regulated at the level of gene rearrangement. repeated rearrangement. Less commonly, the V H in the H chain
Mechanisms that have been shown to contribute to allelic can be replaced by means of rearrangement to a cryptic RSS
exclusion include asynchronous replication of the two alleles, located at the terminus of the V H gene segment.