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理化学研究所 横浜研究所 免疫・アレルギー科学総合研究センターでは以下の3つの

場所:理化学研究所 横浜研究所 北研究棟 RCAI 6階 大セミナー室
講師:Dr. Daniel J. Cua
(Principal Scientist&s_comma; Discovery Research&s_comma; DNAX Research Inc)
The roles of IL-12 and IL-23 in host defense and autoimmune inflammation

場所:理化学研究所 横浜研究所 北研究棟 RCAI 6階 大セミナー室
講師:Dr. Jacques Banchereau
(Director&s_comma; Baylor Institute for Immunology Research)
Assessing and manipulating human immunity through dendritic cells

場所:理化学研究所 横浜研究所 北研究棟 RCAI 6階 大セミナー室
講師: Dr. Makio Iwashima
(Assistant Professor&s_comma; Program in Molecular Immunology&s_comma; Institute of
Molecular Medicine and Genetics&s_comma; Medical College of Georgia)
演題: Ying and Yang of T cell activation

A form of partial activation of T cells is defined as the process that leads
to CD25 expression in the absence of IL-2 production. In the previous
studies&s_comma; we have demonstrated that the signal mediated by Shc and ERK play
critical roles for expression of IL-2 but not for CD25. c-Rel is one of the
downstream targets of this signaling pathway. A detailed analysis on the
ERK function showed that its activity is essential for IL-2 production only
during the late phase of T cell activation and is dispensable during the
initial two hours.
Based on these data&s_comma; we proposed a “Two tier model” of T cell
activation. In this model&s_comma; initial activation signals such as Ca2+
elevation and Ras activation lead to induction of early genes that are
required for CD25 expression. Among the gene products induced during the
early hours&s_comma; a set of molecules is predicted to play roles as the “check
point” factors to ensure that antigenic stimulation is sustained over hours.
These molecules would transduce signals from TCR mediated by ERK during the
late phase and induce IL-2 promoter activation.
To test this model&s_comma; we analyzed proteins that are modified in an ERK
dependent manner during the late phase of T cell activation and identified
heterogeneous nuclear ribonucleoprotein K (hnRNP-K) as a critical molecule
for IL-2 production. Gene knock-down of hnRNP-K resulted in severe
impairment of IL-2 production. Among transcription factors that control the
IL-2 promoter&s_comma; NF-kB was affected most by the loss of hnRNP-K. Notably&s_comma;
gene knock-down of hnRNP-K showed no effect on CD69 and CD25 expression.
hnRNP-K forms a stable complex with Vav&s_comma; which has been shown as a critical
molecule for transcriptional up-regulation of the IL-2 promoter. siRNA of
hnRNP-K(siK) caused a marked increase of caspase-dependent preteolytic
cleavage of Vav protein. Further&s_comma; Vav-induced IL-2 promoter activation was
abrogated by siK. The data showed that hnRNP-K is required for the stability
of Vav protein during the late phase of T cell activation. Loss of the full
length Vav protein is a likely cause of impaired IL-2 production. Together&s_comma;
the data indicate that ERK mediates the late TCR signal via hnRNP-K to
ensure the promoter activity of IL-2 by protecting Vav.

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