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 language | English |
|---|---|
| Pages (from-to) | 8985-8994 |
| Number of pages | 10 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 116 |
| Issue number | 18 |
| DOIs | |
| Publication status | Published - Apr 30 2019 |
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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 journal › Article
}
TY - JOUR
T1 - DNA threads released by activated CD4+ T lymphocytes provide autocrine costimulation
AU - Costanza, Massimo
AU - Poliani, Pietro L.
AU - Portararo, Paola
AU - Cappetti, Barbara
AU - Musio, Silvia
AU - Pagani, Francesca
AU - Steinman, Lawrence
AU - Colombo, Mario P.
AU - Pedotti, Rosetta
AU - Sangaletti, Sabina
PY - 2019/4/30
Y1 - 2019/4/30
N2 - 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.
AB - 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.
KW - Autoimmunity
KW - CD4 T cells
KW - DNA threads
KW - EAE
KW - Multiple sclerosis
UR - http://www.scopus.com/inward/record.url?scp=85065509626&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065509626&partnerID=8YFLogxK
U2 - 10.1073/pnas.1822013116
DO - 10.1073/pnas.1822013116
M3 - Article
C2 - 30988194
AN - SCOPUS:85065509626
VL - 116
SP - 8985
EP - 8994
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 18
ER -