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J. Biol. Chem., Vol. 282, Issue 34, 25152-25158, August 24, 2007

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T Cell Responses in Mammalian Diaphanous-related Formin mDia1 Knock-out Mice^*

Kathryn M. Eisenmann, Richard A. West, Dagmar Hildebrand, Susan M. Kitchen, Jun Peng, Robert Sigler^¶, Jinyi Zhang^||, Katherine A. Siminovitch^||, and Arthur S. Alberts¹

From the Laboratory of Cell Structure and Signal Integration, Flow Cytometry Core Facility, Van Andel Research Institute, Grand Rapids, Michigan 49503, ^¶Esperion Therapeutics, Division of Pfizer, Ann Arbor, Michigan 48108, and ^||Department of Medicine, University of Toronto, Mount Sinai Hospital, Samuel Lunenfeld and Toronto General Hospital Research Institutes, Toronto, Ontario M5G 1X5, Canada

Activated T cells rapidly assemble filamentous (F-) actin networks in response to ligation of the T cell receptor or upon interaction with adhesive stimuli in order to facilitate cell migration and the formation of the immune synapse. Branched filament assembly is crucial for this process and is dependent upon activation of the Arp2/3 complex by the actin nucleation-promoting factor Wiskott-Aldrich Syndrome protein (WASp). Genetic disruption of the WAS gene has been linked to hematopoietic malignancies and various cytopenias. Although the contributions of WASp and Arp2/3 to T cell responses are fairly well characterized, the role of the mammalian Diaphanous (mDia)-related formins, which both nucleate and processively elongate non-branched F-actin, has not been demonstrated. Here, we report the effects on T cell development and function following the knock out of the murine Drf1 gene encoding the canonical formin p140mDia1. Drf1^-/- mice develop lymphopenia characterized by diminished T cell populations in lymphoid tissues. Consistent with a role for p140mDia1 in the regulation of the actin cytoskeleton, isolated Drf1^-/- splenic T cells adhered poorly to extracellular matrix proteins and migration in response to chemotactic stimuli was completely abrogated. Both integrin and chemokine receptor expression was unaffected by Drf1^-/- targeting. In response to proliferative stimuli, both thymic and splenic Drf1^-/- T cells failed to proliferate; ERK1/2 activation was also diminished in activated Drf1^-/- T cells. These data suggest a central role for p140mDia1 in vivo in dynamic cytoskeletal remodeling events driving normal T cell responses.

Received for publication, April 17, 2007 , and in revised form, June 21, 2007.

^* This work was supported by the Van Andel Foundation, the National Cancer Institute (R21 CA107529), and the American Cancer Society (RSG-05-033-01-CSM) (to A. S. A.) and by NRSA Grant F32 GM723313 (to K. M. E.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3, Table S1, and a movie.

¹ To whom correspondence should be addressed: Laboratory of Cell Structure and Signal Integration, Van Andel Research Inst., 333 Bostwick Ave. N.E., Grand Rapids, MI 49503. E-mail: art.alberts{at}vai.org.

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