The Motheaten Mutation Rescues B Cell Signaling and Development in CD45-deficient Mice

The cytosolic SHP-1 and transmembrane CD45 protein tyrosine phosphatases (PTP) play critical roles in regulating signal transduction via the B cell antigen receptor (BCR). These PTPs differ, however, in their effects on BCR function. For example, BCR-mediated mitogenesis is essentially ablated in mice lacking CD45 (CD45(−)), but is enhanced in SHP-1–deficient motheaten (me) and viable motheaten (me(v)) mice. To determine whether these PTPs act independently or coordinately in modulating the physiologic outcome of BCR engagement, we assessed B cell development and signaling in CD45-deficient me(v) (CD45(−)/SHP-1(−)) mice. Here we report that the CD45(−)/SHP-1(−) cells undergo appropriate induction of protein kinase activity, mitogen-activated protein kinase activation, and proliferative responses after BCR aggregation. However, BCR-elicited increases in the tyrosine phosphorylation of several SHP-1–associated phosphoproteins, including CD19, were substantially enhanced in CD45(−)/SHP-1(−), compared to wild-type and CD45(−) cells. In addition, we observed that the patterns of cell surface expression of μ, δ, and CD5, which distinguish the PTP-deficient from normal mice, are largely restored to normal levels in the double mutant animals. These findings indicate a critical role for the balance of SHP-1 and CD45 activities in determining the outcome of BCR stimulation and suggest that these PTPs act in a coordinate fashion to couple antigen receptor engagement to B cell activation and maturation.