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

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T-Lymphocytes
DNA
Autoimmune Experimental Encephalomyelitis
Multiple Sclerosis
Reactive Oxygen Species
Neuromyelitis Optica
Inflammation
Adaptive Immunity
Myelin Sheath
Helper-Inducer T-Lymphocytes
Central Nervous System
Lymph Nodes
Cytokines
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

DNA threads released by activated CD4+ T lymphocytes provide autocrine costimulation. / Costanza, Massimo; Poliani, Pietro L.; Portararo, Paola; Cappetti, Barbara; Musio, Silvia; Pagani, Francesca; Steinman, Lawrence; Colombo, Mario P.; Pedotti, Rosetta; Sangaletti, Sabina.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 18, 30.04.2019, p. 8985-8994.

Research output: Contribution to journalArticle

Costanza, Massimo ; Poliani, Pietro L. ; Portararo, Paola ; Cappetti, Barbara ; Musio, Silvia ; Pagani, Francesca ; Steinman, Lawrence ; Colombo, Mario P. ; Pedotti, Rosetta ; Sangaletti, Sabina. / DNA threads released by activated CD4+ T lymphocytes provide autocrine costimulation. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 18. pp. 8985-8994.
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