Original Article

A Dual Role for Src Homology 2 Domain–containing Inositol-5-Phosphatase (SHIP) in Immunity: Aberrant Development and Enhanced Function of B Lymphocytes in SHIP^-/- Mice

Correspondence to: R. Keith Humphries, Terry Fox Laboratory, 601 W. 10th Ave., Vancouver, British Columbia V5Z 1L3, Canada. Tel:604-877-6070 Fax:604-877-0712 E-mail:keith{at}terryfox.ubc.ca.

Released online: 28 February 2000

In this report, we demonstrate that the Src homology 2 domain–containing inositol-5-phosphatase (SHIP) plays a critical role in regulating both B cell development and responsiveness to antigen stimulation. SHIP^-/- mice exhibit a transplantable alteration in B lymphoid development that results in reduced numbers of precursor B (fraction C) and immature B cells in the bone marrow. In vitro, purified SHIP^-/- B cells exhibit enhanced proliferation in response to B cell receptor stimulation in both the presence and absence of Fc receptor IIB coligation. This enhancement is associated with increased phosphorylation of both mitogen-activated protein kinase and Akt, as well as with increased survival and cell cycling. SHIP^-/- mice manifest elevated serum immunoglobulin (Ig) levels and an exaggerated IgG response to the T cell–independent type 2 antigen trinitrophenyl Ficoll. However, only altered B cell development was apparent upon transplantation into nonobese diabetic–severe combined immunodeficient (NOD/SCID) mice. The in vitro hyperresponsiveness, together with the in vivo findings, suggests that SHIP regulates B lymphoid development and antigen responsiveness by both intrinsic and extrinsic mechanisms.

Key Words: signal transduction, B cell receptor, FcRIIB, immunoglobulin, antigen response

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