Receptor selection in B and T lymphocytes

Abstract

The process of clonal selection is a central feature of the immune system, but immune specificity is also regulated by receptor selection, in which the fate of a lymphocyte's antigen receptor is uncoupled from that of the cell itself. Whereas clonal selection controls cell death or survival in response to antigen receptor signaling, receptor selection regulates the process of V(D)J recombination, which can alter or fix antigen receptor specificity. Receptor selection is carried out in both T and B cells and can occur at different stages of lymphocyte differentiation, in which it plays a key role in allelic exclusion, positive selection, receptor editing, and the diversification of the antigen receptor repertoire. Thus, the immune system takes advantage of its control of V(D)J recombination to modify antigen receptors in such a way that self/non-self discrimination is enhanced. New information about receptor editing in T cells and B-1 B cells is also discussed.

Figure 1

Role of gene organization in facilitating or inhibiting receptor editing. V, D, and J coding elements are flanked by recombination signal sequences carrying 12-bp spacers (open triangles) or 23-bp spacers (black triangles) that constrain the range of possible rearrangements in cis. Recombinase joins elements with 12-bp spacers to those with 23 bp. Because of their overall organization, loci vary in their abilities to support receptor editing type rearrangements. (A) Cartoon of one type of gene organization similar to mouse and human Ig-H loci (see Figure 3 for details). The presence of D elements along with V genes in the same transcriptional orientation as the J/C cluster forces deletional rearrangements. Primary VDJ assembly cannot be replaced by recombination using conventional signal sequences. (B) In contrast, in loci without D elements, sequential rearrangements are often possible. In this example, a primary (1⁰) V4-to-J join is replaced by a subsequent secondary (2⁰) rearrangement between V2 and the downstream J. Such secondary rearrangement permits the replacement of potentially functional V4-to-J joins, i.e., receptor editing. This type of organization is also seen in mammalian TCRα loci.

Figure 2

Gene organizations that inhibit or facilitate receptor editing. (A) Cluster type receptor gene organization is used in many lower vertebrates and is retained in certain mammalian receptor gene loci, such as mouse Ig-λ. Rearrangements occur within clusters but not between adjoining clusters, preventing editing and potentially posing problems for isotype exclusion. (B) Inversional rearrangements are dictated by gene orientation. Variable gene segments in inverted transcriptional orientations relative to J/C clusters are indicated by upside-down Vs. Such elements join though inversion rather than excision of intervening DNA. Hypothetical V3 and V4 elements must undergo deletion during primary rearrangement to Js, whereas V1 and V2 elements rearrange by inversion. Note that subsequent secondary rearrangement can again occur through either deletion or inversion, but inversional rearrangements retain more V genes and change the orientations of V elements intervening the break points.

Figure 3

Antigen receptor loci of (A) mouse and (B) human. Note that Ig-κ, TCR-α, TCR-δ, and TCR-β have structures that are compatible with secondary, replacement rearrangements in both mouse and human. Conventional V(D)J recombination disfavors receptor editing at the Ig-H locus of mouse or human because of the 12/23 rule and the arrangement of V_H elements in the same transcriptional orientation as the J_H/C_H cluster. In the mouse Ig-λ and TCR-γ loci, functionally rearranged genes cannot efficiently be altered by secondary rearrangements because of their cluster type organization, whereas editing is possible in the human versions of these loci provided that the 3′ most J’s are not initially used. In the TCR-δ locus of both mouse and human, TCR-α rearrangements exclude TCR-δ expression.