How persistent infection overcomes peripheral tolerance mechanisms to cause T cell-mediated autoimmune disease

• 成果类型: Article
• 署名作者: Yin, Rose; Melton, Samuel; Huseby, Eric S.; Kardar, Mehran; Chakraborty, Arup K.
• 署名单位: Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); University of Massachusetts System; University of Massachusetts Worcester; Harvard University; Massachusetts Institute of Technology (MIT); Ragon Institute; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Massachusetts Institute of Technology (MIT)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14702
• DOI: 10.1073/pnas.2318599121
• 发表日期: 2024-03-12
• 关键词: major histocompatibility complex; myelin basic-protein; mhc class-i; thymic selection; immune homeostasis; molecular mimicry; virus-infection; beta-cells; self; receptor

摘要

T cells help orchestrate immune responses to pathogens, and their aberrant regulation can trigger autoimmunity. Recent studies highlight that a threshold number of T cells (a quorum) must be activated in a tissue to mount a functional immune response. These collective effects allow the T cell repertoire to respond to pathogens while suppressing autoimmunity due to circulating autoreactive T cells. Our computational studies show that increasing numbers of pathogenic peptides targeted by T cells during persistent or severe viral infections increase the probability of activating T cells that are weakly reactive to self-antigens (molecular mimicry). These T cells are easily re-activated by the self-antigens and contribute to exceeding the quorum threshold required to mount autoimmune responses. Rare peptides that activate many T cells are sampled more readily during severe/persistent infections than in acute infections, which amplifies these effects. Experiments in mice to test predictions from these mechanistic insights are suggested.