Construction of a T cell receptor signaling range for spontaneous development of autoimmune disease

Author:

Tanaka Atsushi123ORCID,Maeda Shinji14ORCID,Nomura Takashi1ORCID,Llamas-Covarrubias Mara Anais56ORCID,Tanaka Satoshi1ORCID,Jin Lin5ORCID,Lim Ee Lyn2ORCID,Morikawa Hiromasa2ORCID,Kitagawa Yohko2ORCID,Akizuki Shuji1ORCID,Ito Yoshinaga1ORCID,Fujimori Chihiro1ORCID,Hirota Keiji12ORCID,Murase Tosei12ORCID,Hashimoto Motomu1ORCID,Higo Junichi7ORCID,Zamoyska Rose8ORCID,Ueda Ryuzo9ORCID,Standley Daron M.5ORCID,Sakaguchi Noriko12ORCID,Sakaguchi Shimon12ORCID

Affiliation:

1. Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan 1

2. Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan 2

3. Department of Frontier Research in Tumor Immunology, Center of Medical Innovation and Translational Research, Graduate School of Medicine, Osaka University, Osaka, Japan 3

4. Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan 4

5. Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan 5

6. Institute of Research in Biomedical Sciences, University Center of Health Sciences, University of Guadalajara, Guadalajara, Mexico 6

7. Institute for Protein Research, Osaka University, Suita, Japan 7

8. Institute for Immunology and Infection Research, The University of Edinburgh, Edinburgh, UK 8

9. Department of Tumor Immunology, Aichi Medical University School of Medicine, Aichi, Japan 9

Abstract

Thymic selection and peripheral activation of conventional T (Tconv) and regulatory T (Treg) cells depend on TCR signaling, whose anomalies are causative of autoimmunity. Here, we expressed in normal mice mutated ZAP-70 molecules with different affinities for the CD3 chains, or wild type ZAP-70 at graded expression levels under tetracycline-inducible control. Both manipulations reduced TCR signaling intensity to various extents and thereby rendered those normally deleted self-reactive thymocytes to become positively selected and form a highly autoimmune TCR repertoire. The signal reduction more profoundly affected Treg development and function because their TCR signaling was further attenuated by Foxp3 that physiologically repressed the expression of TCR-proximal signaling molecules, including ZAP-70, upon TCR stimulation. Consequently, the TCR signaling intensity reduced to a critical range generated pathogenic autoimmune Tconv cells and concurrently impaired Treg development/function, leading to spontaneous occurrence of autoimmune/inflammatory diseases, such as autoimmune arthritis and inflammatory bowel disease. These results provide a general model of how altered TCR signaling evokes autoimmune disease.

Funder

Japan Society for the Promotion of Science

Ministry of Education, Sports, and Culture of Japan

Japan Agency for Medical Research and Development

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

Cited by 8 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3