金沢大学十全医学会学術交流会

＜講演要旨＞金沢大学附属病院泌尿器科・講師　泉　浩二先生「前立腺癌の進展と薬剤耐性化におけるケモカインの役割」、大阪大学大学院医学系研究科内分泌内科代謝学・講師　西澤　均先生 「内臓脂肪蓄積の臨床的意義と内分泌・代謝学」、信州大学名誉教授/地域医療推進学教室特任教授　田中榮司 先生 「B型肝炎診療におけるHBcr抗原測定の意義

Serial analysis of gene expression(SAGE)法を用いた2,3,7,8-tetrachlorodibenzo-p-dioxin(ダイオキシン)曝露マウス肝臓の包括的遺伝子発現解析

取得学位 : 博士（医学）, 学位授与番号 : 医博甲第1527号 , 学位授与年月日 : 平成14年3月31日, 学位授与大学 : 金沢大

The Possible Role of TASK Channels in Rank-Ordered Recruitment of Motoneurons in the Dorsolateral Part of the Trigeminal Motor Nucleus.

Because a rank-ordered recruitment of motor units occurs during isometric contraction of jaw-closing muscles, jaw-closing motoneurons (MNs) may be recruited in a manner dependent on their soma sizes or input resistances (IRs). In the dorsolateral part of the trigeminal motor nucleus (dl-TMN) in rats, MNs abundantly express TWIK (two-pore domain weak inwardly rectifying K channel)-related acid-sensitive-K(+) channel (TASK)-1 and TASK3 channels, which determine the IR and resting membrane potential. Here we examined how TASK channels are involved in IR-dependent activation/recruitment of MNs in the rat dl-TMN by using multiple methods. The real-time PCR study revealed that single large MNs (>35 μm) expressed TASK1 and TASK3 mRNAs more abundantly compared with single small MNs (15-20 μm). The immunohistochemistry revealed that TASK1 and TASK3 channels were complementarily distributed in somata and dendrites of MNs, respectively. The density of TASK1 channels seemed to increase with a decrease in soma diameter while there were inverse relationships between the soma size of MNs and IR, resting membrane potential, or spike threshold. Dual whole-cell recordings obtained from smaller and larger MNs revealed that the recruitment of MNs depends on their IRs in response to repetitive stimulation of the presumed Ia afferents. 8-Bromoguanosine-cGMP decreased IRs in small MNs, while it hardly changed those in large MNs, and subsequently decreased the difference in spike-onset latency between the smaller and larger MNs, causing a synchronous activation of MNs. These results suggest that TASK channels play critical roles in rank-ordered recruitment of MNs in the dl-TMN

The transcription factor BATF operates as an essential differentiation checkpoint in early effector CD8+ T cells

The transcription factor BATF is required for interleukin 17 (IL-17)-producing helper T cell (TH17) and follicular helper T cell (TFH) differentiation. Here, we show that BATF also has a fundamental role in regulating effector CD8+ T cell differentiation. BATF-deficient CD8+ T cells show profound defects in effector expansion and undergo proliferative and metabolic catastrophe early after antigen encounter. BATF, together with IRF4 and Jun proteins, binds to and promotes early expression of genes encoding lineage-specific transcription-factors (T-bet and Blimp-1) and cytokine receptors, while paradoxically repressing genes encoding effector molecules (IFN-γ and granzyme B). Thus, BATF amplifies TCR-dependent transcription factor expression and augments inflammatory signal propagation but restrains effector gene expression. This checkpoint prevents irreversible commitment to an effector fate until a critical threshold of downstream transcriptional activity has been achieved

Long-Term Persistence of Exhausted CD8 T Cells in Chronic Infection Is Regulated by MicroRNA-155

Persistent viral infections and tumors drive development of exhausted T (TEX) cells. In these settings, TEX cells establish an important host-pathogen or host-tumor stalemate. However, TEX cells erode over time, leading to loss of pathogen or cancer containment. We identified microRNA (miR)-155 as a key regulator of sustained TEX cell responses during chronic lymphocytic choriomeningitis virus (LCMV) infection. Genetic deficiency of miR-155 ablated CD8 T cell responses during chronic infection. Conversely, enhanced miR-155 expression promoted expansion and long-term persistence of TEX cells. However, rather than strictly antagonizing exhaustion, miR-155 promoted a terminal TEX cell subset. Transcriptional profiling identified coordinated control of cell signaling and transcription factor pathways, including the key AP-1 family member Fosl2. Overexpression of Fosl2 reversed the miR-155 effects, identifying a link between miR-155 and the AP-1 transcriptional program in regulating TEX cells. Thus, we identify a mechanism of miR-155 regulation of TEX cells and a key role for Fosl2 in T cell exhaustion. During persistent viral infections, exhausted T cells (TEX) erode quantitatively and qualitatively and therefore fail to provide protection. Stelekati et al. identified microRNA (miR)-155 as a key molecule that can enhance and sustain TEX responses long-term during chronic viral infection

The epigenetic landscape of T cell exhaustion.

Exhausted T cells in cancer and chronic viral infection express distinctive patterns of genes, including sustained expression of programmed cell death protein 1 (PD-1). However, the regulation of gene expression in exhausted T cells is poorly understood. Here, we define the accessible chromatin landscape in exhausted CD8+ T cells and show that it is distinct from functional memory CD8+ T cells. Exhausted CD8+ T cells in humans and a mouse model of chronic viral infection acquire a state-specific epigenetic landscape organized into functional modules of enhancers. Genome editing shows that PD-1 expression is regulated in part by an exhaustion-specific enhancer that contains essential RAR, T-bet, and Sox3 motifs. Functional enhancer maps may offer targets for genome editing that alter gene expression preferentially in exhausted CD8+ T cells

金沢大学十全医学会 第4回 学術交流会

松下貴史先生「全身性強皮症におけるB細胞の役割」池森敦子先生「腎疾患診療における尿中L-FABPの有用性と可能性」生水真紀夫先生「進化の視点から理解する

反復感染応答におけるメモリーCD8陽性T細胞集団の老化と維持機構に関する研究

金沢大学医薬保健研究域医学系 / 東京大学様々なサブセットから構成される抗原特異的CTLを、感染応答の回数によって分類する新しい視点から、細胞性免疫記憶の老化現象を解析し、抗原特異的CTL応答の維持機構を解明することを目的とした。樹立したmemory CTL老化モデル用いてnaive CD8、一次、二次memory CTLを分取し、包括的遺伝子発現解析を行った。反復感染応答によるmemory CTLの老化現象は、慢性感染症時に見られるexhaustionとは異なる状態であると推察された。Although it is suggested that the nature of memory CTL changes over repeated antigenic challenges, molecular characteristics of distinct memory CTL with different number of antigen experience are largely unknown. In this study, we analyzed genome wide transcriptome of primary and secondary memory CTL using a next-generation DNA sequencer. Memory CTL changes molecular signature as they experience the responses and memory CTL senescence differs from exhaustion.研究課題/領域番号:20790369, 研究期間(年度):2008-2009出典：研究課題「反復感染応答におけるメモリーCD8陽性T細胞集団の老化と維持機構に関する研究」課題番号20790369（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-20790369/20790369seika/）を加工して作