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© The Rockefeller University Press, 0022-1007/1997/8/581/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 4, August 18, 1997 581-588

Article

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

Giovanni Pani*,{ddagger},§, Katherine A. Siminovitch*,{ddagger},§, and Christopher J. Paige*,||

From the * Department of Immunology, {ddagger} Department of Medicine and Molecular and Medical Genetics, University of Toronto, § The Samuel Lunenfeld Research Institute, Mount Sinai Hospital, and || The Wellesley Hospital Research Institute, Wellesley Hospital, Toronto, Ontario, M4Y 1J3, Canada

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 (mev) 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 mev (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, {delta}, 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.

Address correspondence to Dr. C. Paige, The Wellesley Hospital Research Institute, Wellesley Hospital, 160 Wellesley St. East, Toronto, Ontario M4Y 1J3, Canada. Phone: 416-926-7751; FAX: 416-926-5109; E-mail: Paige{at}whri.on.ca

1 Abbreviations used in this paper: BCR, B cell antigen receptor; HEL, hen egg lysozyme; HRP, horseradish peroxidase; MAP, mitogen-activated protein; me, motheaten; me v, viable motheaten; PTK, protein tyrosine kinase; PTP, protein tyrosine phosphase.


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