Categorical selection of the antibody repertoire in splenic B cells

Abstract

In the bone marrow, the passage of developing B cells through critical checkpoints of differentiation is associated with a reduction of specific categories of CDR3 of the Ig heavy chain (CDR-H3), particularly those with excessive hydrophobic or charged amino acids and those with a length of eight or fewer residues. To gain insight into the role of CDR-H3 content in the development of B cells in the spleen, we compared the sequences of V H 7183DJCl transcripts from sorted transitional T1, marginal zone, and follicular B cell subsets to those expressed by immature IgM + IgD -and mature IgM lo IgD hi B cells in the bone marrow. Although differences in V H utilization were noted, the T1 CDR-H3 repertoire showed extensive similarity to that of immature bone marrow B cells, and the follicular CDR-H3 repertoire most resembled that of mature bone marrow B cells. Unlike the splenic follicular and bone marrow mature B cell CDR-H3 repertoires, the marginal zone B cell CDR-H3 repertoire retained both short and highly charged amino acid motifs, including those with two arginines. Our findings suggest that antigen binding sites containing specific categories of CDR-H3 sequence content may inhibit, permit, or even facilitate passage of the host B cell through critical checkpoints in peripheral as well as central development.

Antibody Repertoire Development in Fetal and Neonatal Piglets: XIX. Undiversified B Cells with Hydrophobic HCDR3s Preferentially Proliferate in the Porcine Reproductive and Respiratory Syndrome

“…Data presented herein show that so-called "polyclonal B cell activation" in this viral infection is instead selective expansion of B cells with hydrophobic HCDR3s that are normally deselected during development (75) to yield an oligoclonal population with hydrophobic HCDR3s. This biased expansion means that the normally dominant, neutral-charged HCDR3 population seen in newborns and other treatment groups (Fig.…”

“…These investigators show that in the mature B cell repertoire, glycine and tyrosine primarily encoded in RF1 are overrepresented and this effect is responsible for the near neutral (0.0 -0.3) population (64). Hydrophobic HCDR3s are found in the T1 repertoire and the immature B cells from which they are derived, but this population is selectively lost in mature, circulating B cells (75).…”

Molecular Dissection of Antibody Responses against Pneumococcal Surface Protein A: Evidence for Diverse DH-Less Heavy Chain Gene Usage and Avidity Maturation

“…3A). This is in contrast to the mouse preimmune repertoire, where the HCDR3 length ranges from five to 20 codons (average ϳ12.5 codons) (36). It is well established that upon encountering the Ag the HCDR3 length range typically narrows down, as a restricted set of CDR3 lengths provides optimum Ag binding.…”

“…Ig molecules that bind B cell epitopes found on the surface of soluble Ags by necessity tend to be hydrophilic. Various studies have speculated that highly hydrophobic HCDR3 are thus less likely to create optimal paratopes (36,47,48). Schroeder and colleagues demonstrated that the mouse mature B cell repertoire uses D H RFs that are rich in the amino acids tyrosine and glycine (49).…”

Porcine Reproductive and Respiratory Syndrome Virus Subverts Repertoire Development by Proliferation of Germline-Encoded B Cells of All Isotypes Bearing Hydrophobic Heavy Chain CDR3

“…2) that preferentially bear BCRs with hydrophobic H chain CDR3 (HCDR3) regions (6). Skewing of hydropathicity profiles toward B cells with hydrophobic binding sites is unusual in mice and humans (7)(8)(9) and was not observed in littermates infected with SIV, sham controls, young pigs infected with helminthic parasites, or in newborn piglets (6). However, that study did not randomly sample B cell clones, so the size of the subpopulation could not estimated and the source of the expanded clones with regard to either V H gene usage or isotype expression was not identified.…”