Peripheral B cell tolerance and function in transgenic mice expressing an IgD superantigen.
Transitional B cells turn over rapidly in vivo and are sensitive to apoptosis upon BCR ligation in vitro. However, little direct evidence addresses their tolerance sensitivity in vivo. A key marker used to distinguish these cells is IgD, which, through alternative RNA splicing of H chain transcripts, begins to be coexpressed with IgM at this stage. IgD is also expressed at high levels on naive follicular (B-2) and at lower levels on marginal zone and B-1 B cells. In this study, mice were generated to ubiquitously express a membrane-bound IgD-superantigen. These mice supported virtually no B-2 development, a greatly reduced marginal zone B cell population, but a relatively normal B-1 compartment. B cell development in the spleen abruptly halted at the transitional B cell population 1 to 2 stage, a block that could not be rescued by either Bcl-2 or BAFF overexpression. The developmentally arrested B cells appeared less mature and turned over more rapidly than nontransgenic T2 cells, exhibiting neither conventional features of anergy nor appreciable receptor editing. Paradoxically, type-2 T-independent responses were more robust in the transgenic mice, although T-dependent responses were reduced and had skewed IgL and IgH isotype usages. Nevertheless, an augmented memory response to secondary challenge was evident. The transgenic mice also had increased serum IgM, but diminished IgG, levels mirrored by the increased numbers of IgM(+) plasma cells. This model should facilitate studies of peripheral B cell tolerance, with the advantages of allowing analysis of polyclonal populations, and of B cells naturally lacking IgD.
Department of Immunology and Microbial Science, Kellogg School of Science and Technology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Bao Hoa
BH
Duong
Takayuki
T
Ota
Djemel
D
Aït-Azzouzene
Miyo
M
Aoki-Ota
José Luis
JL
Vela
Christoph
C
Huber
Kevin
K
Walsh
Amanda L
AL
Gavin
David
D
Nemazee
D000818:Animals; D001324:Autoantigens / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D016026:Bone Marrow Transplantation / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology*; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D007127:Immunoglobulin Constant Regions / Q000378:metabolism; D007072:Immunoglobulin D / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D057127:Single-Chain Antibodies / Q000096:biosynthesis / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D018089:Superantigens / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes / Q000276:immunology
D001324:Autoantigens; D007127:Immunoglobulin Constant Regions; D007072:Immunoglobulin D; D057127:Single-Chain Antibodies; D018089:Superantigens