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J. Biol. Chem., Vol. 283, Issue 36, 24392-24399, September 5, 2008

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T Cell Receptor-mediated Activation of CD4⁺CD44^hi T Cells Bypasses Bcl10

AN IMPLICATION OF DIFFERENTIAL NF-B DEPENDENCE OF NAïVE AND MEMORY T CELLS DURING T CELL RECEPTOR-MEDIATED RESPONSES^*

Hu Zeng, Yuhong Chen, Mei Yu, Liquan Xue^¶, Xiang Gao, Stephan W. Morris^¶, Demin Wang^||, and Renren Wen¹

From the Model Animal Research Center, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 225001, China, The Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin 53226, ^¶Departments of Pathology and Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, and ^||Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

Previous studies have demonstrated that Bcl10 (B-cell leukemia/lymphoma 10) is essential for T cell receptor-mediated NF-B activation and subsequent proliferation and interleukin 2 (IL2) production. However, here we demonstrate that, contrary to expectations, Bcl10 is differentially required for T cell activation, including for both proliferation and cytokine production. When CD4⁺ and CD8⁺ T cells were divided based on expression levels of CD44, which distinguishes naïve cells (CD44^lo) versus those that are antigen-experienced (CD44^hi), IL2 production by and proliferation of CD4⁺CD44^lo naïve cells and both subpopulations of CD8⁺ T cells were clearly Bcl10-dependent, whereas these same functional properties of CD4⁺CD44^hi T cells occurred largely independent of Bcl10. As with the other subpopulations of T cells, CD4⁺CD44^hi T cells did not activate the NF-B pathway in the absence of Bcl10; nevertheless, these CD4⁺CD44^hi antigen-experienced T cells efficiently secreted IL2 after T cell receptor stimulation. Strikingly, therefore, T cell receptor-mediated IL2 production in these cells is NF-B-independent. Our studies suggest that antigen-experienced CD4⁺ T cells differ from their naïve counterparts and from CD8⁺ T cells in their ability to achieve activation independent of the Bcl10/NF-B pathway.

Received for publication, March 25, 2008 , and in revised form, June 17, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants AI52327 (to R. W.), U19 AI062627 pilot grant (to R. W.), HL073284 (to D. W.), CA87064 (NCI, to S. W. M.), and CA21765 (NCI Cancer Center CORE, to L. X. and S. W. M.). This work was also supported by American Cancer Society Grant RSG CCG-106204 (to D. W.) and by the American Lebanese Syrian Associated Charities, St. Jude Children's Research Hospital. 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 To whom correspondence should be addressed: The Blood Research Institute, 8727 Watertown Plank Rd., Milwaukee, WI 53226. Tel.: 414-937-3852; Fax: 414-937-6284; E-mail: renren.wen{at}bcw.edu.

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