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Bcl10/Malt1 Signaling Is Essential for TCR-Induced NF-B Activation in Thymocytes but Dispensable for Positive or Negative Selection¹

Philipp J. Jost^*, Stephanie Weiss^*, Uta Ferch^*, Olaf Gross^*, Tak W. Mak, Christian Peschel^* and Jürgen Ruland^2,*

^* Third Medical Department, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany; and Campbell Family Institute for Breast Cancer Research and Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada

During T cell development in the thymus, high-affinity/avidity TCR engagement induces negative selection by apoptosis, while lower affinity/avidity TCR interactions lead to positive selection and survival of thymocytes. Yet, the mechanisms that discriminate between positive and negative selection are not fully understood. One major regulator of survival and apoptosis in lymphoid cells is the transcription factor NF-B. Several reports have indicated key roles for NF-B in positive and negative selection. In peripheral T cells, TCR ligation activates NF-B through a selective pathway that involves protein kinase C, Bcl10, and Malt1. While protein kinase C is dispensable for thymic TCR signaling, the molecular roles of Bcl10 and Malt1 in thymocytes have not been investigated. In the present study, we show that both Bcl10 and Malt1 are essential for TCR signaling in thymocytes as a genetic disruption of either molecule blocks TCR-induced NF-B activation in these cells. To investigate the function of this pathway in thymic selection, we introduced the Bcl10 or Malt1 mutations into three well-established TCR transgenic mouse models. Surprisingly, using several in vivo or in vitro assays, we were unable to demonstrate a role for TCR-induced NF-B activation in either positive or negative selection. Thus, while TCR signaling to NF-B controls the activation of mature T cells, we suggest that this pathway is not involved in the positive or negative selection of thymocytes.

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.

¹ This work was supported by a Max-Eder-Program grant from Deutsche Krebshilfe and Sonderforschungsbereich grants from Deutsche Forschungsgemeinschaft (to J.R.).

² Address correspondence and reprint requests to Dr. Jürgen Ruland, Third Medical Department of Hematology and Oncology, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Strasse 22, 81675 Munich, Germany. E-mail address: jruland{at}lrz.tum.de

³ Abbreviations used in this paper: DN, double negative; DP, double positive; SP, single positive; IKK, IB kinase; PKC, protein kinase C; Iono, ionophore; 7-AAD, 7-aminoactinomycin D.

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				S. C. Morley, K. S. Weber, H. Kao, and P. M. Allen Protein Kinase C-{theta} Is Required for Efficient Positive Selection J. Immunol., October 1, 2008; 181(7): 4696 - 4708. [Abstract] [Full Text] [PDF]