Developmental changes in the human heavy chain CDR3
M Margarida Souto-Carneiro1, Gary P Sims, Hermann Girschik
1Repertoire Analysis Group, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892-1820, USA.
Insights
Fetal B cells have shorter immunoglobulin heavy chain CDR3 regions due to less TdT enzyme activity and preferential use of specific D segments. These features contribute to developmental changes in the B cell repertoire during ontogeny.
Area of Science:
- Immunology
- Developmental Biology
- Molecular Genetics
Background:
- The complementarity-determining region 3 (CDR3) of the immunoglobulin heavy (Ig H) chain exhibits distinct characteristics in fetal versus adult B cell repertoires.
- Understanding the molecular mechanisms driving these developmental changes is crucial for comprehending B cell maturation.
Purpose of the Study:
- To investigate the mechanisms underlying developmental alterations in the CDR3(H) repertoire.
- To compare nonproductive and productive V(H)DJ(H) rearrangements in fetal and adult B cells to identify selection-independent changes.
Main Methods:
- Analysis of nonproductive V(H)DJ(H) rearrangements from fetal, neonatal, and adult single B cells.
- Comparison of nonproductive rearrangements with corresponding productive repertoires.
- Assessment of TdT activity, D segment usage (specifically D7-27), DJ(H) rearrangements, and junctional microhomology usage.
Main Results:
- Fetal B cells exhibit shorter CDR3(H) primarily due to diminished TdT activity and preferential use of the proximal D segment D7-27.
- The enhanced usage of D7-27 in fetal cells is linked to its locus position rather than its length.
- Fetal B cells show decreased recurrent DJ(H) rearrangements and increased junctional microhomology usage compared to adults, with these patterns shifting during ontogeny.
Conclusions:
- The shorter length and reduced complexity of fetal CDR3(H) result from limited enzymatic modifications and a preference for proximal D and J(H) segments during V(H)DJ(H) recombination.
- These findings highlight key molecular events driving the maturation of the B cell repertoire from fetal to adult stages.
Abstract:
The CDR3 of the Ig H chain (CDR3(H)) is significantly different in fetal and adult repertoires. To understand the mechanisms involved in the developmental changes in the CDR3(H) of Ig H chains, sets of nonproductive V(H)DJ(H) rearrangements obtained from fetal, full-term neonates and adult single B cells were analyzed and compared with the corresponding productive repertoires. Analysis of the nonproductive repertoires was particularly informative in assessing developmental changes in the molecular mechanisms of V(H)DJ(H) recombination because these rearrangements did not encode a protein and therefore their distribution was not affected by selection. Although a number of differences were noted, the major reasons that fetal B cells expressed Ig H chains with shorter CDR3(H) were both diminished TdT activity in the DJ(H) junction and the preferential use of the short J(H) proximal D segment D7-27. The enhanced usage of D7-27 by fetal B cells appeared to relate to its position in the locus rather than its short length. The CDR3(H) progressively acquired a more adult phenotype during ontogeny. In fetal B cells, there was decreased recurrent DJ(H) rearrangements before V(H)-DJ(H) rearrangement and increased usage of junctional microhomologies both of which also converted to the adult pattern during ontogeny. Overall, these results indicate that the decreased length and complexity of the CDR3(H) of fetal B cells primarily reflect limited enzymatic modifications of the joins as well as a tendency to use proximal D and J(H) segments during DJ(H) rearrangements.
Related Concept Videos
02:32Exon Recombination
Exon shuffling follows “splice frame rules.” Each exon has three reading...
02:15M-Cdk Drives Transition Into Mitosis
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...