Immune Response Regulation by Antigen Receptors' Clone-Specific Nonself Parts

Abstract

Antigen determinants (epitopes) are recognized by the combining sites (paratopes) of B and T cell antigen receptors (BCR/TCR), which again express clone-specific epitopes (idiotopes) that can be recognized by BCR/TCR not only of genetically different donors but also within the autologous immune system. While xenogeneic and allogeneic anti-idiotypic BCR/TCR are broadly cross-reactive, only autologous anti-idiotypes are truly specific and of functional regulatory relevance within a particular immune system. Autologous BCR/TCR idiotopes are (a) somatically created at the third complementarity-determining regions, (b) through mutations introduced into BCRs during adaptive immune responses, and (c) through the conformational impact of both. As these idiotypic characters have no genomic counterparts they have to be regarded as antigen receptor-intrinsic nonself-portions. Although foreign, however, they are per se non-immunogenic, but in conjunction with immunogenicity- and adjuvanticity-providing antigen-induced immune responses, they induce abating regulatory idiotypic chain reactions. The dualistic nature of antigen receptors of seeing antigens (self and nonself alike) and being nonself at the same time has far reaching consequences for an understanding of the regulation of adaptive immune responses.

Keywords: B cell antigen receptor (BCR); T cell antigen receptor (TCR); adaptive immune response; idiotype; immunogenicity; regulation; self–nonself; transgenerational imprinting.

Figure 1

Comparison of PubMed entry “idiotype” with related marks per year between 1960 and 2017. The figure shows the results of a PubMed search for the following keywords: idiotype—red filled rhombus; regulatory T cell—yellow open triangles; B cell antigen receptor—blue open squares; T cell antigen receptor—light green open circles.

Figure 2

VDJ gene segments coding for the antibody heavy chain variable region and modifications creating the third complementarity-determining region CDR-H3 of antibodies. CDR-H1 and CDR-H2 are fully encoded in the genomic V_H gene segment. By contrast, CDR-H3 coding sequences are somatically created during recombination of V, D, and J gene segments. During this process, all three segments can be modified by deletion of nucleotides through exonuclease activity, addition of P nucleotides and insertion of N-nucleotides at the two junctions by terminal deoxynucleotidyl transferase. Hence, the D-region in the middle of CDR-H3 does not conform to genomic sequences and may be flanked by non-genetic N/P sequences that do not have an inheritable genomic counterpart.

Figure 3

Modification of VDJ gene segments in anti-hapten antibodies. Homozygous mutant mice containing a single frameshifted DFL16.1 D gene segment (ΔD-DμFS mice derived from BALB/c mice) were immunized with the hapten 2-phenyl-oxazolone (phOx) coupled to chicken serum albumin (87). Monoclonal antibodies (n = 83) were prepared during various stages of primary and memory responses and V region sequences were determined (87). Fifty-eight (~70%) used modified D_H gene sequences and two mAb (~2.5%) reverse D_H sequences. Nucleotide deletion and addition of N/P nucleotides is shown for these two groups of antibodies: (A) nucleotide deletion at 3′-V_H, (B) addition of N/P nucleotides at the V_H-D_H junction, (C) nucleotide deletion at 5′-D_H, (D) nucleotide deletion at 3′-D_H, (E) addition of N/P nucleotides at the D_H-J_H junction, and (F) deletion of nucleotides at 5′-J_H. The medium values of deletion and addition are indicated by broken red lines with a red triangle on top. Antibodies using the genomic configuration at a particular site are represented by gray bars. In 23 additional mAb (~28%), the D_H coding sequence was truncated by exonuclease activity to such an extent that it could not be detected.

Figure 4

Representation of B and T cells by top views of their antigen receptors. B cells are schematically represented by stylized top views of their BCR paratopes as hexagons [based on Ref. (96)] and T cells by hexagonal stars [based on Ref. (97)]. Numbers indicate the complementarity-determining regions 1–3 of V_H, V_L, TCR_α, and TCR_β. BCR/TCR background colors symbolize the specificity of a particular paratope just as the genomic coding of CDR1 and CDR2. The full nonself-quality of CDR3s is indicated by different colors, but the marginal nonself-character of CDR-L3 is not shown.

Figure 5

The adaptive immune response—from clonal selection to nonself-directed idiotypic regulatory clonal connections. Antigen selects epitope-specific B cells and carrier-specific T cells from the respective repertoires. BCR/TCR background colors symbolize the specificity of a particular paratope (see legend to Figure 4), in this example, purple for the B cell epitope-specificity and blue for the carrier-specificity of T cells. After antigen-induced activation, CDR-H3 nonself-idiotopes (white) of antigen-specific idiotype (B1/Ab1—purple paratope) activates nonself-specific anti-idiotypic B cells (Ab2—white paratope) with the help of likewise nonself-specific anti-idiotypic T cells (T1—white paratope). In further reaction, nonself CDR-H3 portions of Ab2 (red) may be recognized and activate anti-anti-idiotypic B cells (Ab3—red paratope) with the help of Ab2-idiotype-specific T cells. This idiotypic cascade may proceed to anti-anti-anti-idiotypes (Ab4) and even further as shown for Ab6 (162). Thus, clonal selection and activation by antigen induces clonal connections of an idiotypic cascade that exerts a regulatory feedback on the ongoing antigen-induced response. During this response, in addition, somatic mutations create new nonself-idiotopes which may also induce an idiotypic feedback regulation. Abbreviations: APC, antigen-presenting cell; MHC, major histocompatibility complex; PC, plasma cell; LLPC, long-lived plasma cells; BM, B memory cell.