CBLB and Autoimmunity: While CBL-B−/− mice display increased sensitivity to development of autoimmunity and CBL−/− mice show normal peripheral T-cell function, CBL/CBL-B double knockout is embryonic lethal and induction of Cre-mediated deletion of a floxed CBL allele by Lck-Cre (deletion at the double negative (DN) stage of thymocyte development) on a CBL-B null background led to severe spontaneous autoimmune organ infiltration, splenomegaly, and auto-antibodies leading to death between 12 and 16 weeks of age [30].