Abnormal Peripheral Lymphocyte Function in c-ablMutant Mice

Abstract

The proto-oncogene c-ablencodes a tyrosine kinase that is hypothesized to function in proliferation–stimulatory signaling pathways. Previous work on mice homozygous for targeted mutations in the c-ablgene (ablm1andabl2mutant strains) has demonstrated multiple defects, including a susceptibility to infections that results in a high mortality rate after weaning. FACS analysis of the hemopoietic system of c-ablmutants demonstrated variable reductions in B and T lymphocytes in adult bone marrow, thymus, spleen, and peripheral blood. In addition, bone marrow from mutants showed a decreased ability to respond to interleukin-7. We further found that B cells fromablm1mice had a reduced ability to respond to lipopolysaccharide (decreased to 10% of control response) that was dependent on the culture conditions and the tissue of origin of B cells. Peripheral blood from the mutants also had a reduced response to the T cell mitogen concanavalin A. Immune response inablm1mice as determined by the mixed lymphocyte response and the sheep red blood cell plaque-forming assay was grossly normal. These findings suggest that although specific signaling pathways in lymphocytes may involve c-Abl, the immune system can function in the absence of a normal c-ablgene product.