International Immunology, Vol. 15, No. 3, pp. 351-357,
March 2003
© 2003 Japanese Society for Immunology
A crucial role of CD4 T cells as a functional source of CD154 in the initiation of insulin-dependent diabetes mellitus in the non-obese diabetic mouse
1 Section of Immunobiology and 2 Howard Hughes Medical Institute, Yale University School of Medicine, PO Box 208011, New Haven, CT 06520-8011, USA 3 Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK 4 JDRF/WT Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke’s Hospital, Cambridge CB2 2XY, UK 5 Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA 6 Present address: Kitasato University School of Medicine, Department of Immunology, 1-15-1 Kitasato, Sagamihara, Kanagawa 288-8555, Japan 7 Present address: Fundació Clínic per a la recerca Biomédica, IDIPAPS, Hopital Clínic I Universitari de la Universitat de Barcelona, Barcelona 08036, Spain
The first two authors contributed equally to this work.
Correspondence to: R. A. Flavell; E-mail: richard.flavell{at}yale.edu
Transmitting editor: A. Cooke
Although the critical requirement of CD4 T cells in type I (insulin-dependent) diabetes mellitus (T1DM) has been well documented, information on the exact role(s) of CD4 T cells in T1DM development is still limited. Here, utilizing non-obese diabetic (NOD) mice deficient for CD154 (CD154-KO/NOD), we have identified a mandatory role of CD4 T cells as the functional source of CD154 in the initiation of T1DM. Without CD154, CD4 T cells were not capable of mediating help in disease development in NOD mice. In fact, full expression of CD154 on the CD4 T cells seems to be essential in the normal spontaneous development of T1DM, since no diabetes was observed in CD154+/– mice in which around half of CD4 T cells do not express CD154 at all, at least by the time they were 40 weeks old. It was also shown that transgenic expression of CD80 on ß cells of pancreatic islets, which is believed to provide ß cells with the ability to prime cytotoxic T lymphocytes specific for islet antigens, did not restore insulitis in CD154-KO/NOD mice. Taken collectively, these results indicated that CD4 T cells play a crucial role in T1DM as a source of CD154, and that the role of CD154 on CD4 T cells in insulitis may not be just to facilitate priming and expanding of auto-reactive CD8 T cells by activating antigen-presenting cells bearing islet antigens.
Keywords: antigen-presenting cell, CD4 T lymphocyte, CD40, insulitis
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