Engagement of CD44 up-regulates Fas Ligand expression on T cells leading to activation-induced cell death |
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Authors: | Kazuhisa Nakano Kazuyoshi Saito Shinichiro Mine Sho Matsushita Yoshiya Tanaka |
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Institution: | (1) Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan;(2) Department of Allergy and Immunology, Saitama Medical University, 38 Morohongo, Moroyama, Japan |
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Abstract: | Activation-induced cell death (AICD) plays a pivotal role in self-tolerance by deleting autoreactive T cells, but a defect
of AICD results in expansion of autoreactive T cells and is deeply involved in the pathogenesis of rheumatoid arthritis. Although
the process of AICD is mainly mediated by Fas Ligand (FasL)/Fas signaling, it remains unclear what induces FasL expression
on T cells. In the present study, we found that CD44 was the most potent stimulator of FasL expression on human peripheral
T cells. CD44 cross-linking rapidly up-regulated FasL expression on the T cell surface by delivery from the cytoplasm without
new FasL protein synthesis. This up-regulation of FasL was mediated by activation of a tyrosine kinase, IP3 receptor-dependent
Ca2+ mobilization and actin cytoskeletal rearrangements. Furthermore, AICD induced by CD3 restimulation was inhibited by hyaluronidase
as well as by soluble Fas, indicating an interaction between membrane-bound hyaluronan and the cell surface CD44 was involved
in the up-regulation of FasL expression on T cells and subsequent AICD. We therefore propose that the engagement of CD44 on
T cells can eliminate autoreactive T cells by expression of FasL and FasL-mediated AICD.
Grant support: Scientific Research by the Ministry of Health, Labor and Welfare of Japan, the Ministry of Education, Culture, Sports, Science
and Technology of Japan and University of Occupational and Environmental Health, Japan. |
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Keywords: | CD44 Hyaluronan T cell Activation-induced cell death Fas ligand Rheumatoid arthritis |
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