Antigen receptor allelic exclusion: an update and reappraisal

Abstract

Most lymphocytes express cell surface Ag receptor chains from single alleles of distinct Ig or TCR loci. Since the identification of Ag receptor allelic exclusion, the importance of this process and the precise molecular mechanisms by which it is achieved have remained enigmatic. This brief review summarizes current knowledge of the extent to which Ig and TCR loci are subject to allelic exclusion. Recent progress in studying and defining mechanistic steps and molecules that may control the monoallelic initiation and subsequent inhibition of V-to-(D)-J recombination is outlined using the mouse TCRβ locus as a model with frequent comparisons to the mouse IgH and Igκ loci. Potential consequences of defects in mechanisms that control Ag receptor allelic exclusion and a reappraisal of the physiologic relevance of this immunologic process also are discussed.

Figure 1. Genomic Configuration of TCRβ, IgH, and Igκ Loci

Schematic diagrams of germline TCRβ, IgH, and Igκ loci depicting the relative locations of V segments (blue rectangles), D segments (yellow rectangles), J segments (green rectangles), constant (C) regions (grey rectangles), enhancers (red ovals), and promoters (blue circles). The relative location of the Igκ Sis element (blue square) also is shown. The loci are not drawn to scale, particularly with regard to the genomic distances between V and D-J segments.

Figure 2. Multiple Redundant and Successive Mechanisms Likely Cooperate to Control Antigen Receptor Allelic Exclusion

Mono-allelic initiation of V-to-(D)-J rearrangement, feedback signals, and maintenance of feedback inhibition likely function together to achieve allelic exclusion of TCRβ, IgH, and Igκ loci. Mono-allelic initiation of V-to-(D)-J rearrangement may be regulated by asynchronous replication, localization, conformations, transcription, and/or histone modifications between TCRβ, IgH, and Igκ loci on homologous chromosomes. Feedback inhibition appears to involve signals that directly prevent V-to-(D)-J rearrangement by down-regulating accessibility, juxtaposition, or RAG binding to antigen receptor loci, and may involve signals that indirectly prevent V-to-(D)-J rearrangement by inactivating RAG activity or silencing germline V segments. Maintenance of feedback inhibition likely is achieved through de-contraction and re-positioning of loci, silencing of germline V segments, and developmental stage-specific expression of factors that promote or inhibit secondary V-to-(D)-J rearrangements.

Figure 3. Potential “Lateral Inhibition” of V(D)J Recombination may Contribute to Enforce Allelic Exclusion

RAG cleavage of antigen receptor loci in developing lymphocytes activates ATM dependent signals that may transiently inhibit additional V(D)J recombination events. This regulation may enable time for DNA repair, transcription, translation, surface expression, and signaling required for feedback inhibition. These putative ATM signals could directly prevent V-to-(D)J rearrangements or indirectly, such as through down-regulation of RAG activity.