DNA threads released by activated CD4+ T lymphocytes provide autocrine costimulation

Massimo Costanza, Pietro L. Poliani, Paola Portararo, Barbara Cappetti, Silvia Musio, Francesca Pagani, Lawrence Steinman, Mario P. Colombo, Rosetta Pedotti, Sabina Sangaletti

Research output: Contribution to journalArticle

Abstract

The extrusion of DNA traps contributes to a key mechanism in which innate immune cells clear pathogens or induce sterile inflammation. Here we provide evidence that CD4+ T cells, a critical regulator of adaptive immunity, release extracellular threads of DNA on activation. These DNA extrusions convey autocrine costimulatory signals to T lymphocytes and can be detected in lymph nodes isolated during the priming phase of experimental autoimmune encephalomyelitis (EAE), a CD4+ T cell-driven mouse model of multiple sclerosis. Pharmacologic inhibition of mitochondrial reactive oxygen species (mtROS) abolishes the extrusion of DNA by CD4+ T cells, reducing cytokine production in vitro and T cell priming against myelin in vivo. Moreover, mtROS blockade during established EAE markedly ameliorates disease severity, dampening autoimmune inflammation of the central nervous system. Taken together, these experimental results elucidate a mechanism of intrinsic immune costimulation mediated by DNA threads released by activated T helper cells, and identify a potential therapeutic target for such disorders as multiple sclerosis, neuromyelitis optica, and CD4+ T cell-mediated disorders.

Original languageEnglish
Pages (from-to)8985-8994
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number18
DOIs
Publication statusPublished - Apr 30 2019

Keywords

  • Autoimmunity
  • CD4 T cells
  • DNA threads
  • EAE
  • Multiple sclerosis

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'DNA threads released by activated CD4<sup>+</sup> T lymphocytes provide autocrine costimulation'. Together they form a unique fingerprint.

  • Cite this