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. 2024 Mar 12;121(11):e2318599121.
doi: 10.1073/pnas.2318599121. Epub 2024 Mar 6.

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

Rose Yin #  1 , Samuel Melton #  2 , Eric S Huseby  3 , Mehran Kardar  2 , Arup K Chakraborty  1   2   4   5
Affiliations

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

Rose Yin et al. Proc Natl Acad Sci U S A. .

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.

Keywords: T cells; autoimmunity; immunology.

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Conflict of interest statement

Competing interests statement:A.K.C. is a consultant (titled Academic Partner) for Flagship Pioneering, serves as consultant and on the Strategic Oversight Board of its affiliated company, Apriori Bio, and is a consultant and SAB member of another affiliated company, Metaphore Bio. The other authors declare no competing interest.

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