Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 191, Issue 5, Pages 781-794Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.191.5.781
Keywords
signal transduction; B cell receptor; Fc gamma RIIB; immunoglobulin; antigen response
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In this report, we demonstrate that the Src homology 2 domain-containing inositol-5-phosphatase (SHIP) plays a critical role in regulating bath B cell development and responsiveness to antigen stimulation. SHIP-/- Nice exhibit a transplantable alteration in B lymphoid development that results in reduced numbers of precursor a (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 gamma 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.
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