Immunoglobulin heavy chain expression shapes the B cell receptor repertoire in human B cell development.
Developing B cells must pass a series of checkpoints that are regulated by membrane-bound Ig(mu) through the Igalpha-Igbeta signal transducers. To determine how Ig(mu) expression affects B cell development and Ab selection in humans we analyzed Ig gene rearrangements in pro-B cells from two patients who are unable to produce Ig(mu) proteins. We find that Ig(mu) expression does not affect V(H), D, or J(H) segment usage and is not required for human Igkappa and Iglambda recombination or expression. However, the heavy and light chains found in pro-B cells differed from those in peripheral B cells in that they showed unusually long CDR3s. In addition, the Igkappa repertoire in Ig(mu)-deficient pro-B cells was skewed to downstream Jkappas and upstream Vkappas, consistent with persistent secondary V(D)J rearrangements. Thus, Ig(mu) expression is not required for secondary V(D)J recombination in pro-B cells. However, B cell receptor expression shapes the Ab repertoire in humans and is essential for selection against Ab's with long CDR3s.
Meffre
E
E
Laboratory of Molecular Immunology, The Rockefeller University, Howard Hughes Medical Institute, New York, New York, USA. meffree@mail.rockefeller.edu
Milili
M
M
Blanco-Betancourt
C
C
Antunes
H
H
Nussenzweig
M C
MC
Schiff
C
C
D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D016022:Case-Control Studies; D002454:Cell Differentiation; D002675:Child, Preschool; D022801:Complementarity Determining Regions / Q000235:genetics; D005260:Female; D015870:Gene Expression; D015322:Gene Rearrangement, B-Lymphocyte; D006720:Homozygote; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000235:genetics; D007148:Immunoglobulin mu-Chains / Q000235:genetics*; D007136:Immunoglobulins / Q000172:deficiency; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology; D007223:Infant; D008297:Male; D009154:Mutation; D014158:Transcription, Genetic
D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D007148:Immunoglobulin mu-Chains; D007136:Immunoglobulins