VprBP is required for efficient editing and selection of Igκ+ B cells but is dispensable for Igλ+ and marginal zone B cell maturation and selection

摘要

B cell development past the pro-B cell stage in mice requires the Cul4-DDB1-Roc1 E3 ubiquitin ligase substrate recognition subunit VprBP. Enforced Bcl2 expression overcomes defects in distal VH-DJH and secondary Vκ-Jκ rearrangement associated with VprBP-insufficiency in B cells, and substantially rescues maturation of marginal zone and Igλ⁺ B cells, but not Igκ⁺ B cells. In this background, expression of a site-directed Igκ light chain transgene increases Igκ⁺ B cell frequency, suggesting VprBP does not regulate light chain expression from a productively rearranged Igk allele. In site-directed anti-dsDNA heavy chain transgenic mice, loss of VprBP function in B cells impairs selection of Igκ “editor” light chains typically arising through secondary Igk rearrangement, but not selection of Igλ editor light chains. Both heavy and light chain site-directed transgenic mice show increased B cell anergy when VprBP is inactivated in B cells. Taken together, these data argue that VprBP is required for the efficient receptor editing and selection of Igκ⁺ B cells, but is largely dispensable for Igλ⁺ B cell development and selection, and that VprBP is necessary to rescue autoreactive B cells from anergy induction.