Modulation of the IL-7 dose-response threshold during pro-B cell differentiation is dependent on pre-B cell receptor expression.
The IL-7R and the pre-B cell receptor (pre-BCR) each provide critical signals during differentiation of B cell precursors. In this study we examine the interplay between signals dependent upon these receptors. We demonstrate that pre-BCR-deficient pro-B cells differ significantly from controls in their ability to use the IL-7R. We show that this difference, characterized by a failure to proliferate in response to IL-7, is narrowly restricted to IL-7 concentrations in the picogram per milliliter range and can be overcome with increasing amounts of IL-7. Restoration of Ig heavy chain to recombinase-activating gene-2-deficient pro-B cells leads to a restored response to picogram per milliliter levels of IL-7, providing strong evidence that modulation of the IL-7 dose-response threshold is dependent on pre-BCR. Culture of normal pro-B cells under low IL-7 conditions leads to selective outgrowth of cells expressing mu heavy chain, suggesting that modulation of IL-7 dose-response thresholds can allow for selective expansion of pre-BCR+ cells under conditions where IL-7 is limiting. We also provide evidence that expression of pre-BCR on pro-B cells limits the duration of IL-7 responsiveness by causing differentiation to an IL-7-unresponsive pre-B cell stage. Thus, the pre-BCR-dependent modulation of IL-7 responsiveness affects both the dose-response threshold and the duration of IL-7-induced clonal expansion. Our results suggest that positive selection of pre-BCR+ pro-B cells may be achieved through the fine tuning of IL-7 responses.
Marshall
A J
AJ
Ontario Cancer Institute and Department of Immunology, University of Toronto, Canada.
Fleming
H E
HE
Wu
G E
GE
Paige
C J
CJ
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D001854:Bone Marrow Cells; D002454:Cell Differentiation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D002999:Clone Cells; D003593:Cytoplasm / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D004306:Dose-Response Relationship, Immunologic; D015322:Gene Rearrangement, B-Lymphocyte; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007148:Immunoglobulin mu-Chains / Q000096:biosynthesis; D015851:Interleukin-7 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007700:Kinetics; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis*; D013234:Stem Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors
D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; D007148:Immunoglobulin mu-Chains; D015851:Interleukin-7; C499308:Rag2 protein, mouse; D011947:Receptors, Antigen, B-Cell; C064655:V(D)J recombination activating protein 2