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J. Biol. Chem., Vol. 280, Issue 27, 25621-25628, July 8, 2005

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Membrane Cholesterol Content Accounts for Developmental Differences in Surface B Cell Receptor Compartmentalization and Signaling^*

Fredrick G. Karnell, Randall J. Brezski, Leslie B. King, Michael A. Silverman, and John G. Monroe

From the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160

Recent studies argue for an important role for cholesterol in maintaining plasma membrane heterogeneity and influencing a variety of cellular processes, including signaling, adhesion, and permeability. Here, we document that tolerance-sensitive transitional immature B cells maintain significantly lower membrane unesterified cholesterol levels than mature-stage splenic B cells. In addition, the relatively low level of cholesterol in transitional immature B cells impairs compartmentalization of their B cell receptor (BCR) into cholesterol-enriched domains following BCR aggregation and reduces their ability to sustain certain aspects of BCR signaling as compared with mature B cells. These studies establish an unexpected difference in the lipid composition of peripheral transitional immature and mature B cells and point to a determining role for development-associated differences in cholesterol content for the differential responses of these B cells to BCR engagement.

Received for publication, March 22, 2005 , and in revised form, April 26, 2005.

^* This work was supported by Training Grant AI055428 (to F. G. K.) and Grants AI43620 and AI32592 from the National Institutes of Health (to J. G. M. and R. J. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

To whom correspondence should be addressed: University of Pennsylvania, 421 Curie Blvd., BRB2/3, Rm. 311, Philadelphia, PA 19104. Tel.: 215-898-2873; Fax: 215-573-2014; E-mail: monroej{at}mail.med.upenn.edu.

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