研究者の方へ / For researchers
レクチン受容体を介する異物認識機構とその意義
私たちの研究室では、からだを守る免疫システムの研究を進めています。中でも、外敵の侵入や、からだの異変を速やかに察知する免疫受容体（レセプター）の機能の解明に注力しています。こうした研究の過程で、近年、病原体や損傷自己成分を認識するレクチン受容体群を見出しました。現在、この研究成果を、より効率的な免疫賦活化、並びに、過剰な免疫応答に伴う疾患の治療に繋げる努力を続けています。
Sensing pathogens and damaged self via lectin family receptors
The aim of our laboratory is to study the immune system that protects our body, with particular attention given to immune receptors that immediately sense pathogen invasion and aberrant self. During the course of our research, the receptor that recognizes an important component of Mycobacterium tuberculosis was firstly identified. Now, we are making an effort to implement these results in more efficient immunoactivating strategies, as well as in the treatment of diseases caused by excessive immune responses.
References
Nagata M, Toyonaga K, Ishikawa E, Haji S, Okahashi N, Takahashi M, Izumi Y, Imamura A, Takano K, Ishida H, Nagai S, Illarionov P, Stocker B, Timmer MS, Smith DGM, Williams SJ, Bamba T, Miyamoto T, Arita M, Appelmelk BJ, Yamasaki S. Helicobacter pylori metabolites exacerbate gastritis through C-type lectin receptors.
J. Exp. Med. 218(1): e20200815, 2021
Imai T, MatsumuraT, Mayer-Lambertz S, Wells CA, Ishikawa E, Butcher SK, Barnett TC, Walker MJ, Imamura A, Ishida H, Ikebe T, MiyamotoT, Ato M, Ohga S, Lepenies B, va Sorge NM, Yamasaki S. Lipoteichoic acid anchor triggers Mincle to dribe protective immunity against invasive group A Streptococcus infection.
Proc. Natl. Acad. Sci. USA. 115(45):E10662-71, 2018
Nagata M, Izumi Y, Ishikawa E, Kiyotake R, Doi R, Iwai S, Omahdi Z, Yamaji T, Miyamoto T, Bamba T, Yamasaki S. Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity.
Proc. Natl. Acad. Sci. USA. 114(16): E3285-94. 2017
Ishikawa E, Mori D, Yamasaki S. Recognition of Mycobacterial Lipids by Immune Receptors.
Trends Immunol. 38: 66-76. 2017
#Behler-Janbeck F, #Takano T, Maus R, Stolper J, Jonigk D, Tort Tarrés M, Fuehner T, Prasse A, Welte T, Timmer MS, Stocker BL, Nakanishi Y, Miyamoto T, *Yamasaki S, *Maus UA. C-type Lectin Mincle Recognizes Glucosyl-diacylglycerol of Streptococcus pneumoniae and Plays a Protective Role in Pneumococcal Pneumonia.
PLoS Pathog. 12(12): e1006038. 2016
Toyonaga K, Torigoe S, Motomura Y, Kamichi T, Hayashi JM, Morita YS, Noguchi N, Chuma Y, Kiyohara H, Matsuo K, Tanaka H, Nakagawa Y, Sakuma T, Ohmuraya M, Yamamoto T, Umemura M, Matsuzaki G, Yoshikai Y, Yano I, Miyamoto T, Yamasaki S. C-Type Lectin Receptor DCAR Recognizes Mycobacterial Phosphatidyl-InositolMannosides to Promote a Th1 Response during Infection.
Immunity 45: 1245-57. 2016
Yonekawa A, Saijo S, Hoshino Y, Miyake Y, Ishikawa E, Suzukawa M, Inoue H, Tanaka M, Yoneyama M, Oh-hora M, Akashi K, Yamasaki S. Dectin-2 is a direct receptor for mannose-capped lipoarabinomannan of mycobacteria.
Immunity 41(3): 402-13. 2014
Miyake Y, Toyonaga K, Mori D, Kakuta S, Hoshino Y, Oyamada A, Yamada H, Ono K, Suyama M, Iwakura Y, Yoshikai Y, Yamasaki S. C-Type lectin MCL is an FcRγ-coupled receptor that mediates the adjuvanticity of mycobacterial cord factor.
Immunity 38(5): 1050-62. 2013
Ishikawa T, Itoh F, Yoshida S, Saijo S, Matsuzawa T, Gonoi T, Saito T, Okawa Y, Shibata N, Miyamoto T, Yamasaki S. Identification of distinct ligands for the C-type lectin receptors Mincle and Dectin-2 in the pathogenic fungus Malassezia.
Cell Host Microbe 13(4): 477-88. 2013
T細胞分化における自己識別機構とその意義
胸腺細胞は、"ゆるい"セレクション（β-selection）と厳しいセレクション（positive/negative selection）を組み合わせることによって、「多様性」と「特異性」という一見相反する特性を有するT cell receptor（TCR）レパトアを形成しています。これらは、プレTCR、TCRを介して制御されていますが、その詳細な分子機構には不明な点が多くあります。我々は、生体がどのような分子機構で、戦略の異なる２つのセレクションを巧妙に制御しているのかを明らかにしたいと考えています。
Regulation of T cell development by self recognition via TCR/pre-TCR
Thymocytes must pass through a “loose” selection (β-selection) and a strict selection (positive/negative selection), to finally gain both “diversity” and “specificity”. These processes are regulated through the pre-TCR and TCR; however, the detailed molecular mechanism is still unclear. Our group works toward the elucidation of the means by which our body elegantly orchestrates these two opposite types of selections that have different mechanisms and objectives.
References
Ishikawa E, Kosako H, Yasuda T, Ohmuraya M, Araki K, Kurosaki T, Saito T, Yamasaki S. Protein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1.
Nat. Commun. 7: 12756. 2016
Ishikawa E, Miyake Y, Hara H, Saito T, Yamasaki S. Germ-line elimination of electric charge on pre-T-cell receptor (TCR) impairs autonomous signaling for beta-selection and TCR repertoire formation.
Proc. Natl. Acad. Sci. USA. 107:19979-19984, 2010
*Yamasaki S. and Saito, T. Molecular basis for pre-TCR-mediated autonomous signaling.
Trends.Immunol. 28: 39-43, 2007
Yamasaki S, Ishikawa E, Sakuma M, Ogata K, Sakata-Sogawa K, Hiroshima M, Wiest DL, Tokunaga M, Saito,T. Mechanistic basis of pre-T cell receptor-mediated autonomous signaling critical for thymocyte development.
Nat. Immunol. 7(1): 67-75, 2006
SARS-CoV-2に対するT細胞応答の解析
Studies on T cell immunity against SARS-CoV-2
Through the single cell TCR- and RNA-sequencing, we identified public cTfh clonotypes expanded in recovered COVID-19 patients and determined their epitopes in the specific regions of spike protein conserved among emerging SARS-CoV-2 variants, which are condidates for booster antigens.
References
Lu X, Hosono Y, Nagae M, Ishizuka S, Ishikawa E, Motooka D, Ozaki Y, Sax N, Maeda Y, Kato Y, Morita T, Shinnakasu R, Inoue T, Onodera T, Matsumura T, Shinkai M, Sato T, Nakamura S, Mori S, Kanda T, Nakayama EE, Shioda T, Kurosaki T, Takeda K, Kumanogoh A, Arase H, Nakagami H, Yamashita K, Takahashi Y, Yamasaki S. Identification of conserved SARS-CoV-2 spike epitopes that expand public cTfh clonotypes in mild COVID-19 patients.
J. Exp. Med. 218: e20211327, 2021
