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Deficient Natural Killer Dendritic Cell Responses Underlay the Induction of Theiler's Virus-Induced Autoimmunity.

Chastain EM, Getts DR, Miller SD - MBio (2015)

Bottom Line: Viral infection is an important cofactor, along with genetic susceptibility, in the initiation of a variety of organ-specific autoimmune diseases.Thus, in-depth understanding of how virus infections trigger autoimmunity may lead to novel ways to prevent or treat these diseases.Theiler's murine encephalitis virus-induced demyelinating disease (TMEV-IDD) serves as an important model for the human T cell-mediated autoimmune demyelinating disease multiple sclerosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

No MeSH data available.


Related in: MedlinePlus

Peripheral NKDCs traffic to the CNS after TMEV infection in a VLA-4-dependent manner. (A) Scheme of adoptive transfer experimental design. Congenic B6 CD45.1 splenocytes were transferred intravenously (i.v.) into CD45.2 WT B6 mice 2 days prior to i.c. TMEV infection. Brains and spleens were harvested 3 days p.i. and analyzed for the presence of CD45.1 donor cells. (B) Representative flow plots of CD11c and NK1.1 expression on CD45.1+ cells in the brain and spleen of TMEV- or sham-infected mice. (C) The percentage of transferred donor CD45.1+ cells and CD45.1+ CD11c+ NK1.1+ is quantitated. (D) Quantification of total CNS lymphocytes and NKDCs (CD3− CD45+ CD11c+ NK1.1+ DX5+) 3 days p.i. in TMEV-infected B6 mice treated with the isotype control (black bars) or anti-VLA-4 (white bars) 6 h prior to infection. Data are representative of 2 independent experiments with 5 mice per group. Error bars show standard deviations. ***, P < 0.001; **, P < 0.01; *, P < 0.05.
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fig3: Peripheral NKDCs traffic to the CNS after TMEV infection in a VLA-4-dependent manner. (A) Scheme of adoptive transfer experimental design. Congenic B6 CD45.1 splenocytes were transferred intravenously (i.v.) into CD45.2 WT B6 mice 2 days prior to i.c. TMEV infection. Brains and spleens were harvested 3 days p.i. and analyzed for the presence of CD45.1 donor cells. (B) Representative flow plots of CD11c and NK1.1 expression on CD45.1+ cells in the brain and spleen of TMEV- or sham-infected mice. (C) The percentage of transferred donor CD45.1+ cells and CD45.1+ CD11c+ NK1.1+ is quantitated. (D) Quantification of total CNS lymphocytes and NKDCs (CD3− CD45+ CD11c+ NK1.1+ DX5+) 3 days p.i. in TMEV-infected B6 mice treated with the isotype control (black bars) or anti-VLA-4 (white bars) 6 h prior to infection. Data are representative of 2 independent experiments with 5 mice per group. Error bars show standard deviations. ***, P < 0.001; **, P < 0.01; *, P < 0.05.

Mentions: Given that accumulation of NKDCs in the CNS correlated with activation and proliferation of splenic NKDCs, we hypothesized that the spleen may serve as reservoir of NKDCs, which upon infection migrate out of the spleen and into the brain. To address this hypothesis, congenic B6 CD45.1 bulk splenocytes were adoptively transferred to wild-type (WT) CD45.2 B6 mice. After 2 days, mice were i.c. infected with TMEV, and then brains and spleens were analyzed on day 3 p.i. (Fig. 3A). We found that there was no difference in trafficking of CD45.1 NKDCs to the spleens of either sham- or TMEV-infected animals. However, NKDCs from the donor spleen only migrated to the brain in TMEV-infected animals (Fig. 3B and C). Interestingly, though the percentage of transferred cells was only a small percentage of CNS leukocytes, NKDCs made up a significant proportion of the transferred cells. These data highlight the fact that splenic NKDCs are capable of trafficking to the CNS after infection and are preferentially recruited during infection.


Deficient Natural Killer Dendritic Cell Responses Underlay the Induction of Theiler's Virus-Induced Autoimmunity.

Chastain EM, Getts DR, Miller SD - MBio (2015)

Peripheral NKDCs traffic to the CNS after TMEV infection in a VLA-4-dependent manner. (A) Scheme of adoptive transfer experimental design. Congenic B6 CD45.1 splenocytes were transferred intravenously (i.v.) into CD45.2 WT B6 mice 2 days prior to i.c. TMEV infection. Brains and spleens were harvested 3 days p.i. and analyzed for the presence of CD45.1 donor cells. (B) Representative flow plots of CD11c and NK1.1 expression on CD45.1+ cells in the brain and spleen of TMEV- or sham-infected mice. (C) The percentage of transferred donor CD45.1+ cells and CD45.1+ CD11c+ NK1.1+ is quantitated. (D) Quantification of total CNS lymphocytes and NKDCs (CD3− CD45+ CD11c+ NK1.1+ DX5+) 3 days p.i. in TMEV-infected B6 mice treated with the isotype control (black bars) or anti-VLA-4 (white bars) 6 h prior to infection. Data are representative of 2 independent experiments with 5 mice per group. Error bars show standard deviations. ***, P < 0.001; **, P < 0.01; *, P < 0.05.
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Related In: Results  -  Collection

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fig3: Peripheral NKDCs traffic to the CNS after TMEV infection in a VLA-4-dependent manner. (A) Scheme of adoptive transfer experimental design. Congenic B6 CD45.1 splenocytes were transferred intravenously (i.v.) into CD45.2 WT B6 mice 2 days prior to i.c. TMEV infection. Brains and spleens were harvested 3 days p.i. and analyzed for the presence of CD45.1 donor cells. (B) Representative flow plots of CD11c and NK1.1 expression on CD45.1+ cells in the brain and spleen of TMEV- or sham-infected mice. (C) The percentage of transferred donor CD45.1+ cells and CD45.1+ CD11c+ NK1.1+ is quantitated. (D) Quantification of total CNS lymphocytes and NKDCs (CD3− CD45+ CD11c+ NK1.1+ DX5+) 3 days p.i. in TMEV-infected B6 mice treated with the isotype control (black bars) or anti-VLA-4 (white bars) 6 h prior to infection. Data are representative of 2 independent experiments with 5 mice per group. Error bars show standard deviations. ***, P < 0.001; **, P < 0.01; *, P < 0.05.
Mentions: Given that accumulation of NKDCs in the CNS correlated with activation and proliferation of splenic NKDCs, we hypothesized that the spleen may serve as reservoir of NKDCs, which upon infection migrate out of the spleen and into the brain. To address this hypothesis, congenic B6 CD45.1 bulk splenocytes were adoptively transferred to wild-type (WT) CD45.2 B6 mice. After 2 days, mice were i.c. infected with TMEV, and then brains and spleens were analyzed on day 3 p.i. (Fig. 3A). We found that there was no difference in trafficking of CD45.1 NKDCs to the spleens of either sham- or TMEV-infected animals. However, NKDCs from the donor spleen only migrated to the brain in TMEV-infected animals (Fig. 3B and C). Interestingly, though the percentage of transferred cells was only a small percentage of CNS leukocytes, NKDCs made up a significant proportion of the transferred cells. These data highlight the fact that splenic NKDCs are capable of trafficking to the CNS after infection and are preferentially recruited during infection.

Bottom Line: Viral infection is an important cofactor, along with genetic susceptibility, in the initiation of a variety of organ-specific autoimmune diseases.Thus, in-depth understanding of how virus infections trigger autoimmunity may lead to novel ways to prevent or treat these diseases.Theiler's murine encephalitis virus-induced demyelinating disease (TMEV-IDD) serves as an important model for the human T cell-mediated autoimmune demyelinating disease multiple sclerosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

No MeSH data available.


Related in: MedlinePlus