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