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J. Biol. Chem., Vol. 278, Issue 30, 27836-27843, July 25, 2003

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Proteome Analysis Reveals Caspase Activation in Hyporesponsive CD4 T Lymphocytes Induced in Vivo by the Oral Administration of Antigen^*

Tomohiro Kaji  , Satoshi Hachimura  ¶, Wataru Ise  and Shuichi Kaminogawa  ||

From the Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan and the ^||Department of Food Science and Technology, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa-shi, Kanagawa 252-8510, Japan

The oral administration of antigen can lead to systemic antigen-specific hyporesponsiveness, also known as oral tolerance. This phenomenon is a representative form of immune tolerance to exogenous antigen under physiological conditions. We have previously reported that long term feeding of dietary antigen to ovalbumin-specific T cell receptor (TCR) transgenic mice induced oral tolerance of peripheral T cells with impairment in their TCR-induced calcium-signaling pathway. In this study, we utilized two-dimensional electrophoresis to compare intracellular protein expression patterns of orally tolerant and unsensitized CD4 T cells. We detected 26 increased and 16 decreased protein spots and identified 35 of these by mass spectrometry. The results indicated that the expression of caspases was up-regulated and that the protein levels of intact proteins susceptible to caspase cleavage, such as Grb2-related adaptor downstream of Shc (GADS), were decreased in orally tolerant CD4 T cells. Western blotting experiments confirmed that expression of the active form of caspase-3 and the antiapoptotic factor, X-linked inhibitor of apoptosis, were both up-regulated in orally tolerant CD4 T cells, which were found to be nonapoptotic. We further demonstrated that orally tolerant CD4 T cells could not form normal TCR signaling complexes associated with GADS and showed down-regulated phospholipase C-1 activation, which is likely to contribute to the impairment of TCR-induced calcium signaling. Our findings indicate that orally tolerant CD4 T cells up-regulate caspase activation and show decreased levels of caspase-targeted proteins, including TCR signaling-associated molecules, while up-regulating antiapoptotic factors, all of which appear to contribute to their unique tolerant characteristics.

Received for publication, December 17, 2002 , and in revised form, April 28, 2003.

^* This work was supported by Grant-in-aid for Creative Scientific Research 13GS0015, grants-in-aid for Scientific Research, the Japan Society for the Promotion of Science, and Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists. 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.

Present address: Dept. of Immunology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.

^¶ To whom correspondence should be addressed. Tel.: 81-3-5841-5137; Fax: 81-3-5841-8029; E-mail: ahachi{at}mail.ecc.u-tokyo.ac.jp.

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				W. Ise, K. Nakamura, N. Shimizu, H. Goto, K. Fujimoto, S. Kaminogawa, and S. Hachimura Orally Tolerized T Cells Can Form Conjugates with APCs but Are Defective in Immunological Synapse Formation J. Immunol., July 15, 2005; 175(2): 829 - 838. [Abstract] [Full Text] [PDF]