Replication history of B lymphocytes reveals homeostatic proliferation and extensive antigen-induced B cell expansion.
The contribution of proliferation to B lymphocyte homeostasis and antigen responses is largely unknown. We quantified the replication history of mouse and human B lymphocyte subsets by calculating the ratio between genomic coding joints and signal joints on kappa-deleting recombination excision circles (KREC) of the IGK-deleting rearrangement. This approach was validated with in vitro proliferation studies. We demonstrate that naive mature B lymphocytes, but not transitional B lymphocytes, undergo in vivo homeostatic proliferation in the absence of somatic mutations in the periphery. T cell-dependent B cell proliferation was substantially higher and showed higher frequencies of somatic hypermutation than T cell-independent responses, fitting with the robustness and high affinity of T cell-dependent antibody responses. More extensive proliferation and somatic hypermutation in antigen-experienced B lymphocytes from human adults compared to children indicated consecutive responses upon additional antigen exposures. Our combined observations unravel the contribution of proliferation to both B lymphocyte homeostasis and antigen-induced B cell expansion. We propose an important role for both processes in humoral immunity. These new insights will support the understanding of peripheral B cell regeneration after hematopoietic stem cell transplantation or B cell-directed antibody therapy, and the identification of defects in homeostatic or antigen-induced B cell proliferation in patients with common variable immunodeficiency or another antibody deficiency.
van Zelm
Menno C
MC
Erasmus MC, Department of Immunology, 3015 GE Rotterdam, Netherlands.
Szczepanski
Tomasz
T
van der Burg
Mirjam
M
van Dongen
Jacques J M
JJ
D000293:Adolescent; D000328:Adult; D000818:Animals; D000941:Antigens / Q000502:physiology*; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004261:DNA Replication / Q000276:immunology*; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007145:Immunoglobulin kappa-Chains / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL
D000941:Antigens; D007145:Immunoglobulin kappa-Chains