Clonal Progression during the T Cell-Dependent B Cell Antibody Response Depends on the Immunoglobulin DH Gene Segment Repertoire

Abstract

The diversity of the third complementarity determining region of the IgH chain is constrained by natural selection of immunoglobulin diversity (DH) sequence. To test the functional significance of this constraint in the context of thymus-dependent (TD) immune responses, we immunized BALB/c mice with WT or altered DH sequence with 2-phenyloxazolone-coupled chicken serum albumin (phOx-CSA). We chose this antigen because studies of the humoral immune response to the hapten phOx were instrumental in the development of the current theoretical framework on which our understanding of the forces driving TD responses is based. To allow direct comparison, we used the classic approach of generating monoclonal Ab (mAb) from various stages of the immune response to phOx to assess the effect of changing the sequence of the DH on clonal expansion, class switching, and affinity maturation, which are hallmarks of TD responses. Compared to WT, TD-induced humoral IgM as well as IgG antibody production in the D-altered ΔD-DμFS and ΔD-iD strains were significantly reduced. An increased prevalence of IgM-producing hybridomas from late primary, secondary, and tertiary memory responses suggested either impaired class switch recombination (CSR) or impaired clonal expansion of class switched B cells with phOx reactivity. Neither of the D-altered strains demonstrated the restriction in the VH/VL repertoire, the elimination of VH1 family-encoded antibodies, the focusing of the distribution of CDR-H3 lengths, or the selection for the normally dominant Ox1 clonotype, which all are hallmarks of the anti-phOx response in WT mice. These changes in clonal selection and expansion, as well as CSR indicate that the genetic constitution of the DH locus, which has been selected by evolution, can strongly influence the functional outcome of a TD humoral response.

Humoral Immune Reconstitution Kinetics after Allogeneic Hematopoietic Stem Cell Transplantation in Children: A Maturation Block of IgM Memory B Cells May Lead to Impaired Antibody Immune Reconstitution

“…Allo-HSCT recipients with cGVHD have no detectable T cell receptor excision circlescontaining cells, indicating an absence of thymic function, resulting in limited T cell receptor breadth [58]. Thus, allo-HSCT recipients with cGVHD may show a reduced frequency of CD4 + T cells, with subsequent lack of immunoglobulin class switching [59]. The use of steroid and other immunosuppressant therapy for management of cGVHD might also be a factor in the delayed B cells reconstitution among recipients with GVHD [2].…”

The sequences encoded by immunoglobulin diversity (DH) gene segments play key roles in controlling B‐cell development, antigen‐binding site diversity, and antibody production

“…As proof of the principle that alteration of CDR‐H3 content could alter secondary responses to antigen, we tested the impact of limiting the CDR‐H3 repertoire to a single D H on the antibody response to 2‐phenyl oxazolone (PhOx) coupled to chicken serum albumin (PhOx‐CSA), a T‐dependent antigen . Repeated booster injections of PhOx‐CSA generated a predominantly IgG response in WT mice as expected.…”

HIV-1 gp140 epitope recognition is influenced by immunoglobulin DH gene segment sequence

“…However, the ΔD-iD titers had dropped to ΔD-DFL levels, which were intermediate between ΔD-DμFS and WT. For both 4E10 and Sp400 described above, while recognition was clearly affected by the 3 rd boost, the limited duration of antibody production and the lack of persistence of antibody with boosting could be affected by mechanisms totally different from epitope recognition, e.g., the inability of the ΔD-iD mice to be further boosted or to mount a long lived plasma cell response (Trad et al, 2014). …”