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

Rose Yin, Samuel Melton, Eric S. Huseby, Mehran Kardar, Arup K. Chakraborty

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article numbere2318599121
JournalProceedings of the National Academy of Sciences of the United States of America
Volume121
Issue number11
DOIs
StatePublished - 12 Mar 2024
Externally publishedYes

Bibliographical note

Publisher Copyright:
Copyright © 2024 the Author(s). Published by PNAS.

Keywords

  • immunology
  • | T cells
  • | autoimmunity

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