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Immune Response (Somatic Mutation/Antibody Affinity/Combinational Diversity/Clonal Selection/Network Regulation) LAWRENCE WYSOCKI, TIM MANSER, and MALCOLM L

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Immune Response (Somatic Mutation/Antibody Affinity/Combinational Diversity/Clonal Selection/Network Regulation) LAWRENCE WYSOCKI, TIM MANSER, and MALCOLM L Proc. Natl. Acad. Sci. USA Vol. 83, pp. 1847-1851, March 1986 Immunology Somatic evolution of variable region structures during an immune response (somatic mutation/antibody affinity/combinational diversity/clonal selection/network regulation) LAWRENCE WYSOCKI, TIM MANSER, AND MALCOLM L. GEFTER Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139 Communicated by Herman N. Eisen, October 17, 1985 ABSTRACT Immunization of strain A mice with p- the hapten, p-azophenylarsonate (Ars). An average of50% of azophenylarsonate-conijugated protein stimulates B cells that the anti-Ars antibodies obtained from hyperimmunized strain synthesize anti-p-azophenylarsonate antibodies. A large frac- A mice are serologically related by cross-reaction with a V tion of these cells produce antibodies with variable (V) regions region-specific antiserum that defines the predominant strain encoded by a single heavy chain V gene segment together with A cross-reactive idiotype, denoted as CRI-A or IdCR (13-15). multiple combinations of diversity, heavy chain joining, light Limitations on the serologically defined idiotype as a phe- chain variable, and light chain joining gene segments. Early in notypic marker for clonally related antibodies, however, the immune response, these V regions are not somatically have prompted us to analyze V regions by determining their mutated. One of these V regions is initially expressed by only primary structures and the V gene segment combinations a minority of the responding B cells but binds p-azophenylar- encoding them. This methodology allows us to monitor the sonate with the highest affinity. After a secondary immuniza- selection of related of B cells and to tion, B cells synthesizing mutated derivatives of this single V clonally populations region dominate the response and bind p-azophenylarsonate correlate selection of these clones with the structures and with even higher afflinity than does the unmutated V region. affinities of their receptor antibody V regions. These results suggest that antigen directs both the expression of We sampled B cells participating in the anti-Ars immune the immune repertoire and the amplification of V region response by generating hybridomas during primary and diversity by a sequential process of clonal selection of B cells secondary immune responses and characterized the V region expressing receptor antibodies encoded by unmutated V genes, structures of the antibodies they secrete with respect to the induction of mutation in the V genes expressed by the selected V gene segment combinations encoding them, somatic mu- cells, and reselection of B cells expressing antibodies with tation, and affinity for Ars. Our results demonstrate a strong mutated V regions of higher affinity. correlation between clonal "success"-i.e., a B-cell clone whose Ig product constitutes a significant fraction of serum The antigen specificity of an Ig is determined by the amino antibodies-and affinity for Ars. Clonal success appears to be acid sequence ofits heavy (H) and light (L) chain variable (V) determined by both information encoded in the germ line and region domains. Antibody diversity is generated, in part, by information stochastically generated by somatic mutation. the combinational assembly of five V gene segments during the construction of complete V genes (reviewed in ref. 1). A MATERIALS AND METHODS complete H chain V domain results from the joining of VH, diversity (D), and H chain joining (JH) gene segments. Antigens. Keyhole limpet hemocyanin (KLH) was pur- Similarly, the L chain V domain is fashioned by the apposi- chased from Calbiochem, and a peptide fragment containing tion of VL and JL gene segments. Additional diversity is the amino-terminal 102 amino acids of the phage X repressor generated at the junctions between V gene segments during protein was provided by Robert T. Sauer. Both ofthese were assembly (2-4) and by an unknown mechanism resulting in conjugated with the diazonium salt of Ars as reported (16). nucleotide replacements (termed "somatic mutation") (5-8). Fusions. All fusions were performed between splenic cells The latter mechanism amplifies the potential V region diver- and the Sp2/0-Ag-14 cell line (17) as reported (18) by a sity to an almost limitless extent. modification of an earlier procedure (19). A single B cell synthesizes antibodies with homogeneous V Hybridoma Cell Lines. Primary immune response hybrid- domains and expresses some of these as cell-surface recep- omas were obtained by fusion of A/J spleen cells (on the day tors. Binding of antigen to these receptor antibodies consti- indicated in Table 1) after a single intraperitoneal injection of tutes part of a signal that induces proliferation, resulting in a 300 pug of antigen in complete Freund's adjuvant. For the population that synthesizes antibodies encoded by a uniform production of secondary immune response hybridomas, A/J combination of V gene segments (9-12). While a general mice were immunized intraperitoneally with 250 gg of Ars- scheme of somatically generated antibody diversity has been KLH in complete Freund's adjuvant, were administered a elucidated, we lack an understanding of how this diversity is booster 25 days later with Ars-KLH (200 ug) in saline, and utilized during the initial process of clonal selection and the were sacrificed 3 days later for splenic fusion. subsequent acquisition of functional immunity. Initial at- Serological Assays. IdCR-bearing and Ars-binding antibod- tempts to identify clonally related V regions during an ies were detected in standard RIAs (20). immune response were dependent exclusively on serological methods (idiotype analysis). Abbreviations: Ars, p-azophenylarsonate; KLH, Keyhole limpet The idiotype investigated here is reproducibly elicited in hemocyanin; L, light; H, heavy; V, variable; VH, H chain V segment; strain A mice by immunization with proteins conjugated with VK, kappa L chain V segment; D, diversity segment; JH, H chain joining segment; CK and JK, K L chain constant and J segments; IdcR, strain A major cross-reactive idiotype; VHIdCR, the VH that encodes The publication costs of this article were defrayed in part by page charge Id' antibodies; VKIdCR, the VK that encodes the dominant class ofIdcR payment. This article must therefore be hereby marked "advertisement" antibodies; DI, the D segment of the dominant class of IdcR antibod- in accordance with 18 U.S.C. §1734 solely to indicate this fact. ies; kb, kilobase pair(s). 1847 Downloaded by guest on September 30, 2021 1848 Immunology: Wysocki et al. Proc. Natl. Acad. Sci. USA 83 (1986) Affinity Determinations. Fluorescence quenching measure- ed that seven ofthe nine hybridoma antibodies are apparently ments were performed at 220C with Ars-coupled N-acetyl-L- encoded by a single combination of V gene segments: tyrosine as reported (21). VHIdCR JH2, VKIdcR, JK1 and a D segment (DCR) whose Nucleic Acid Probes. A probe from the VH gene segment product has the deduced amino acid sequence Ser-Xaa-Tyr- that encodes IdfR antibodies, which we call VHIdc1, was Tyr-Gly-Gly-Ser-Tyr-Xaa, where Xaa denotes positions of isolated as a 0.133-kilobase-pair (kb) Ava II-Rsa I fragment variability that occur at junctions of V segment assembly encoding amino acids 15 through 59 (8). A JH (0.7 kb) probe (Fig. 1). The differences between these seven hybridoma was isolated as the nearest Xba I-EcoRI fragment located 3' proteins and the remaining two were confined exclusively to ofthe JH4 gene segment. A 0.9-kb K L chain VK probe (kindly the D region. provided by M. Shapiro and M. Weigert) covering the 5' 276 The V gene segment combination encoding the seven nucleotides of the VKio gene segment and 0.63 kb of 5' homologous V regions characterized here agrees with previ- flanking sequence was used to identify the VK segment that ous amino acid sequence data obtained from the analyses of encodes the dominant class of IdCR antibodies, VKIdCR. A J, hybridoma antibodies isolated during secondary immune probe (2.6 kb) covering the entire cluster ofJK gene segments responses to Ars on the basis of serological criteria alone: of was provided by T. Imanishi-Kari. A probe for the K L chain 16 IdCR antibodies examined, all were found to use the constant (C) region gene (Coj was provided by A. Bothwell. VHIdCR and JH2 gene segments (8, 25, 26, 28, 29); of 9 For use in hybridization analyses, all probes were labeled sequenced IdCR D regions, 8 correspond to the DCR sequence with 32P by nick-translation to a specific activity of 1-2 x 101 (26, 30); 13 IdCR antibodies possess extremely homologous cpm4&g. amino-terminal VK amino acid sequences, and 8 completely Hybridization Analyses. For the purpose of identifying sequenced chains have identical JK amino acid sequences (28, hybridomas transcribing the vHIdC gene segment, whole- 30-32), consistent with the use of either the Jhi or JK2 gene cell lysates from hybridomas grown in replicate 96-well segments. By these combined results, we estimate that microtiter trays were immobilized on nitrocellulose and between 701% and 95% of the antibodies that are synthesized hybridized with the VHIdCR probe as described (18). during the secondary immune response to Ars and that are VH and JH gene segment usage was determined by hybrid- partially encoded by the VHIdCR gene segment are also ization of VHIdCR and JH probes to EcoRI-digested hybrid- encoded by the DCR, JH2, VKIdCR, and JK1 gene segments. oma DNAs as reported (22) by a modification of an earlier Because this combination of V gene segments apparently procedure (8). encodes the serum antibodies that have been identified as the The expressed VKIdCRJK, gene segment combination was major IdCR, we use the term "canonical" to refer to it and the identified by hybridization of HindII- or BamHI-digested IdCR V region structures it encodes.
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