title: Scarcity of lambda 1 B cells in mice with a single point mutation in C lambda 1 is due to a low BCR signal caused by misfolded lambda 1 light chain.
abstract: The presence of valine-154 instead of glycine in the constant region of lambda1 causes a severe lambda1 B cell defect in SJL and lambda1-valine knock-in mice with a compensatory increase in lambda2,3 B cells. The defect is due to low signaling by the lambda1-valine BCR. lambda1-Valine B cells deficient in the SHP-1 phosphatase survive better than lambda2,3 B cells in these mice, or lambda1 B cells in lambda1 wildtype mice. Low signaling is apparently due to misfolding of the lambda1-valine light chain as demonstrated by the absence of a regular beta-sheet structure determined by circular dichroism, the sedimentation of the light chain in solution, and the association of valine-valine constant regions in a yeast two-hybrid assay. lambda1-Valine B cells that survive apparently have a higher BCR signal, presumably because of their specific lambda1-heavy chain combination or having encountered a high-affiniy antigen. lambda1-Valine mice have increased B1 cells which were shown by others to have a higher signaling potential. Valine mice crossed with non-conventional gamma2b transgenic mice, in which B cell development is accelerated and in which B1 cells and high signaling cells are greatly reduced, have essentially no, lambda2,3 B cells, but increased numbers of lambda1-valine B cells. This supports the conclusion that the major defect in lambda1-valine mice is the inability of valine-preB cells to produce a threshold signal for B cell development. The reduction of lambda2,3 B cells in valine mice with a gamma2b transgene shows that the majority of their compensatory increase is almost entirely of the B1 cell type.
authors.affiliation: Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Veronica V
authors.initials: VV
authors.lastname: Volgina
authors.forename: Tianhe
authors.initials: T
authors.lastname: Sun
authors.forename: Grazyna
authors.initials: G
authors.lastname: Bozek
authors.forename: Terence E
authors.initials: TE
authors.lastname: Martin
authors.forename: Ursula
authors.initials: U
authors.lastname: Storb
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D007127:Immunoglobulin Constant Regions / Q000096:biosynthesis / Q000235:genetics*; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000096:biosynthesis / Q000235:genetics*; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017354:Point Mutation / Q000235:genetics*; D017510:Protein Folding; D011947:Receptors, Antigen, B-Cell / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D019076:Transgenes / Q000276:immunology
chemical_list: D007127:Immunoglobulin Constant Regions; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D011947:Receptors, Antigen, B-Cell