Resolution of three nonproliferative immature splenic B cell subsets reveals multiple selection points during peripheral B cell maturation.
Although immature/transitional peripheral B cells may remain susceptible to selection pressures before full maturation, the nature and timing of these selection events remain unclear. We show that correlated expression of surface (s) IgM (sIgM), CD23, and AA4 defines three nonproliferative subpopulations of immature/transitional peripheral B cells. We designate these populations transitional (T) 1 (AA4(+)CD23(-)sIgM(high)), T2 (AA4(+)CD23(+)sIgM(high)), and T3 (AA4(+)CD23(+)sIgM(low)). Cells within all three subsets are functionally immature as judged by their failure to proliferate following sIgM cross-linking in vitro, and their rapid rate of turnover in vivo as assessed by 5-bromo-2'-deoxyuridine labeling. These labeling studies also reveal measurable cell loss at both the T1-T2 and T2-T3 transitions, suggesting the existence of multiple selection points within the peripheral immature B cell pool. Furthermore, we find that Btk-deficient (xid) mice exhibit an incomplete developmental block at the T2-T3 transition within the immature B cell pool. This contrasts markedly with lyn(-/-) mice, which exhibit depressed numbers but normal ratios of each immature peripheral B cell subset and severely reduced numbers of mature B cells. Together, these data provide evidence for multiple selection points among immature peripheral B cells, suggesting that the B cell repertoire is shaped by multiple unique selection events that occur within the immature/transitional peripheral B cell pool.
Allman
D
D
Department of Pathology and Laboratory Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. dallman@mail.med.upenn.edu
Lindsley
R C
RC
DeMuth
W
W
Rudd
K
K
Shinton
S A
SA
Hardy
R R
RR
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000145:classification / Q000276:immunology*; D001973:Bromodeoxyuridine / Q000737:chemistry; D019070:Cell Lineage; D002478:Cells, Cultured; D005260:Female; D018960:Hyaluronan Receptors; D007075:Immunoglobulin M / Q000378:metabolism; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D024101:Mitochondrial Proteins; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011951:Receptors, Complement / Q000378:metabolism; D017455:Receptors, IgE / Q000378:metabolism; D013154:Spleen / Q000276:immunology*; D013234:Stem Cells / Q000276:immunology; D019061:src-Family Kinases / Q000235:genetics
C490193:C1qbp protein, mouse; D018960:Hyaluronan Receptors; D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; D024101:Mitochondrial Proteins; D011951:Receptors, Complement; D017455:Receptors, IgE; C032402:complement 1q receptor; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D001973:Bromodeoxyuridine