Language：English   Publishing type：Research paper (scientific journal)  

Lymphocytes such as CD4+ T cells and B cells mainly infiltrate the salivary glands; however, the precise roles and targets of autoreactive T cells and autoantibodies in the pathogenesis of Sjögren's Syndrome (SS) remain unclear. This study was designed to clarify the role of autoreactive T cells and autoantibodies at the single-cell level involved in the development of sialadenitis. Infiltrated CD4+ T and B cells in the salivary glands of a mouse model resembling SS were single-cell-sorted, and their T cell receptor (TCR) and B cell receptor (BCR) sequences were analyzed. The predominant TCR and BCR clonotypes were reconstituted in vitro, and their pathogenicity was evaluated by transferring reconstituted TCR-expressing CD4+ T cells into Rag2-/- mice and administering recombinant IgG in vivo. The reconstitution of Th17 cells expressing TCR (#G) in Rag2-/- mice resulted in the infiltration of T cells into the salivary glands and development of sialadenitis, while an autoantibody (IgGr22) was observed to promote the proliferation of pathogenic T cells. IgGr22 specifically recognizes double-stranded RNA (dsRNA) and induces the activation of dendritic cells, thereby enhancing the expression of IFN signature and inflammatory genes. TCR#G recognizes antigens related to the gut microbiota. Antibiotic treatment severely reduces the activation of TCR#G-expressing Th17 cells and suppresses sialadenitis development. These data suggest that the anti-dsRNA antibodies and, TCR recognizing the gut microbiota involved in the development of sialadenitis like SS. Thus, our model provides a novel strategy for defining the roles of autoreactive TCR and autoantibodies in the development and pathogenesis of SS.

DOI： 10.1016/j.clim.2024.110258

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

T cells play an important role in the acquired immune response, with regulatory T cells (Tregs) serving as key players in immune tolerance. Tregs are found in nonlymphoid and damaged tissues and are referred to as "tissue Tregs". They have tissue-specific characteristics and contribute to immunomodulation, homeostasis, and tissue repair through interactions with tissue cells. However, important determinants of Treg tissue specificity, such as antigen specificity, tissue environment, and pathology, remain unclear. In this study, we analyzed Tregs in the central nervous system of mice with ischemic stroke and experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. The gene expression pattern of brain Tregs in the EAE model was more similar to that of ischemic stroke Tregs in the brain than to that of spinal cord Tregs. In addition, most T-cell receptors (TCRs) with high clonality were present in both the brain and spinal cord. Furthermore, Gata3+ and Rorc+ Tregs expressed TCRs recognizing MOG in the spinal cord, suggesting a tissue environment conducive to Rorc expression. Tissue-specific chemokine/chemokine receptor interactions in the spinal cord and brain influenced Treg localization. Finally, spinal cord- or brain-derived Tregs had greater anti-inflammatory capacities in EAE mice, respectively. Taken together, these findings suggest that the tissue environment, rather than pathogenesis or antigen specificity, is the primary determinant of the tissue-specific properties of Tregs. These findings may contribute to the development of novel therapies to suppress inflammation through tissue-specific Treg regulation.

DOI： 10.1186/s12974-024-03144-1

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Language：English   Publishing type：Research paper (scientific journal)  

T cell exhaustion impairs tumor immunity and contributes to resistance against immune checkpoint inhibitors. The nuclear receptor subfamily 4 group A (NR4a) family of nuclear receptors plays a crucial role in driving T cell exhaustion. In this study, we observe that NR4a1 and NR4a2 deficiency in CD8+ tumor-infiltrating lymphocytes (TILs) results in potent tumor eradication and exhibits not only reduced exhaustion characteristics but also an increase in the precursors/progenitors of exhausted T (Pre-Tex) cell fraction. Serial transfers of NR4a1-/-NR4a2-/-CD8+ TILs into tumor-bearing mice result in the expansion of TCF1+ (Tcf7+) stem-like Pre-Tex cells, whereas wild-type TILs are depleted upon secondary transfer. NR4a1/2-deficient CD8+ T cells express higher levels of stemness/memory-related genes and illustrate potent mitochondrial oxidative phosphorylation. Collectively, these findings suggest that inhibiting NR4a in tumors represents a potent immuno-oncotherapy strategy by increasing stem-like Pre-Tex cells and reducing exhaustion of CD8+ T cells.

DOI： 10.1016/j.celrep.2024.113898

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.celrep.2023.112940

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Alzheimer's disease (AD) is one of the neurodegenerative diseases and characterized by the appearance and accumulation of amyloid-β (Aβ) aggregates and phosphorylated tau with aging. The aggregation of Aβ, which is the main component of senile plaques, is closely associated with disease progression. AppNL-G-F mice, a mouse model of AD, have three familial AD mutations in the amyloid-β precursor gene and exhibit age-dependent AD-like symptoms and pathology. Gut-brain interactions have attracted considerable attention and inflammatory bowel disease (IBD) has been associated with a higher risk of dementia, especially AD, in humans. However, the underlying mechanisms and the effects of intestinal inflammation on the brain in AD remain largely unknown. Therefore, we aimed to investigate the effects of intestinal inflammation on AD pathogenesis. METHODS: Wild-type and AppNL-G-F mice at three months of age were fed with water containing 2% dextran sulfate sodium (DSS) to induce colitis. Immune cells in the brain were analyzed using single-cell RNA sequencing (scRNA-seq) analysis, and the aggregation of Aβ protein in the brain was analyzed via immunohistochemistry. RESULTS: An increase in aggregated Aβ was observed in the brains of AppNL-G-F mice with acute intestinal inflammation. Detailed scRNA-seq analysis of immune cells in the brain showed that neutrophils in the brain increased after acute enteritis. Eliminating neutrophils by antibodies suppressed the accumulation of Aβ, which increased because of intestinal inflammation. CONCLUSION: These results suggest that neutrophils infiltrate the AD brain parenchyma when acute colitis occurs, and this infiltration is significantly related to disease progression. Therefore, we propose that neutrophil-targeted therapies could reduce Aβ accumulation observed in early AD and prevent the increased risk of AD due to colitis.

DOI： 10.1186/s41232-023-00257-7

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Language：Japanese   Publisher：(株)先端医学社  

近年,神経系の発達において免疫細胞の重要性が明らかになっており,免疫系の異常が神経発達に影響をもたらす可能性がある.自閉スペクトラム症(ASD)は,言語やコミュニケーション・社会的行動の障害,定行動,興味,および活動の限定的で反復的なパターンを特徴とする脳の発達障害である.遺伝子変異やコピー数変異(CNV)などの遺伝的要因や,妊娠中の感染症による母体免疫系の活性化などの環境的要因によって発症する.また,多くのASD患者で免疫機能障害と行動特性の関連が示されている.本稿では,ASDの発症における免疫系の影響に関する最近の知見について概説する.(著者抄録)

Language：Japanese   Publisher：(公社)日本薬理学会  

主要な免疫特権部位である脳においては,他末梢臓器と比較して免疫の研究はあまり盛んではなかった.しかしながら脳はミクログリアと呼ばれる免疫細胞で散りばめられており,とりわけ疾患時には重要な役割を果たす.また疾患時には末梢からも免疫細胞が浸潤する.加えて近年,脳に隣接する組織中の免疫細胞の解析も進み,多くの記述的知見が得られている.しかしながら解析が進むほど,このような免疫応答は症状改善における正と負の両方の作用を持つ複雑な反応であることが明らかとなり,未だに全容の解明には程遠くはっきりとした臨床応用の方向性も定まらないままである.本特集では定常状態に加え,日本の死亡および後遺症を引き起こす主要な原因である脳梗塞,および認知症の実に6～7割を占めるアルツハイマー病におけるミクログリアおよびマクロファージの役割について紹介する.(著者抄録)

Language：English   Publisher：(公社)日本生化学会  

Language：Japanese   Publisher：(株)羊土社  

脳梗塞に伴う炎症は、細胞が壊死したときに放出されるDAMPsとよばれる細胞成分がまず発症1日目に浸潤する炎症性マクロファージを活性化することで進行する。しかし梗塞発症4日目を過ぎるとDAMPsはマクロファージにより急速に細胞内に取り込まれ分解され、炎症が収束に向かう。DAMPsの受容体としてタイプAスカベンジャー受容体MSR1を見出し、さらにMSR1の発現を促進する転写因子としてMafbを単離した。脳内炎症の促進と収束に性質の異なるマクロファージが関与することが明らかとなり、これを利用した新しい治療戦略が提示された。(著者抄録)

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