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

Autor:	Yin R; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139., Melton S; Physics of Living Systems, Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139., Huseby ES; Basic Pathology, Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655., Kardar M; Physics of Living Systems, Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139., Chakraborty AK; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.; Physics of Living Systems, Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139.; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139.; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Mar 12; Vol. 121 (11), pp. e2318599121. Date of Electronic Publication: 2024 Mar 06.
DOI:	10.1073/pnas.2318599121
Abstrakt:	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. Competing Interests: 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.
Databáze:	MEDLINE
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