BCR-induced cell death of B cells from CD22 deficient mice is mediated by a novel ssRNA-directed endonuclease (136.33)

Abstract

Abstract B cells from CD22 deficient mice backcrossed onto a C57BL/6 genetic background (B6 CD22-/-) undergo B cell antigen receptor (BCR)-induced apoptosis. By contrast, B cells from parental inbred CD22-/- mice on a mixed B6x129 genetic background (B6/129 CD22-/-) survive and proliferate normally following BCR ligation. Through an extensive reverse genetic screen, a single locus was identified as being responsible for the proliferation defect of B6 CD22-/- B cells. In B6 CD22-/- mice this locus was homozygous for B6 germline DNA (locusB6), and in B6/129 CD22-/- mice this region was homozygous for 129 germline DNA (locus129). In locusB6 CD22-/- B cells, a novel single-stranded RNA (ssRNA)-directed endonuclease was specifically overexpressed compared to locus129 CD22-/- B cells, suggesting a direct role in BCR-induced cell death. Targeted disruption of the endonuclease gene in locusB6 CD22-/- mice restored BCR-mediated B cell survival and proliferation to normal levels. These results identify a novel ssRNA-directed endonuclease as a potent inhibitor of B cell survival when expressed following antigen receptor stimulation. This research was supported by NIH grant R01CA096547.