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

ABSTRACT The initiating events in autoimmune disease remain to be completely understood, but it is thought that genetic predisposition synergizes with “environmental” factors, including viral infection, leading to disease. One elegant animal model used to study the pathogenesis of multiple sclerosis...

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Autores principales:	Emily M. L. Chastain, Daniel R. Getts, Stephen D. Miller
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Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/cab09de284014cf6b9139d177615e0ee
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spelling	oai:doaj.org-article:cab09de284014cf6b9139d177615e0ee2021-11-15T15:41:26ZDeficient Natural Killer Dendritic Cell Responses Underlay the Induction of Theiler's Virus-Induced Autoimmunity10.1128/mBio.01175-152150-7511https://doaj.org/article/cab09de284014cf6b9139d177615e0ee2015-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01175-15https://doaj.org/toc/2150-7511ABSTRACT The initiating events in autoimmune disease remain to be completely understood, but it is thought that genetic predisposition synergizes with “environmental” factors, including viral infection, leading to disease. One elegant animal model used to study the pathogenesis of multiple sclerosis that perfectly blends genetics and environmental components in the context of virus-induced autoimmunity is Theiler's murine encephalitis virus-induced demyelinating disease (TMEV-IDD). TMEV-infected disease-susceptible SJL/J mice develop a persistent central nervous system (CNS) infection and later develop autoimmune demyelination, while disease-resistant C57BL/6 (B6) mice rapidly clear the infection and develop no autoimmune pathology. Mice of the (B6 × SJL/J)F1 cross between these two mouse strains are classified as intermediately susceptible. We employed this model to investigate if rapid virus clearance in B6 versus SJL/J mice was perhaps related to differences in the innate immune response in the CNS of the two strains in the first few days following intracerebral virus inoculation. Here we show that SJL/J mice lack, in addition to NK cells, a novel innate immune subset known as natural killer dendritic cells (NKDCs), which express phenotypic markers (CD11cint NK1.1+) and functional activity of both NK cells and DCs. These NKDCs are activated in the periphery and migrate into the infected CNS in a very late antigen 4 (VLA-4)-dependent fashion. Most significantly, NKDCs are critical for CNS clearance of TMEV, as transfer of NKDCs purified from B6 mice into TMEV-IDD-susceptible (B6 × SJL/J)F1 mice promotes viral clearance. Together the findings of this work show for the first time a link between NKDCs, viral infection, and CNS autoimmunity. IMPORTANCE 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. Induction of TMEV-IDD is genetically controlled as SJL/J mice develop persistent central nervous system (CNS) infection leading to chronic autoimmune demyelination, while C57BL/6 mice rapidly clear virus and are disease resistant. We determined that, as opposed to resistant B6 mice, disease-susceptible SJL/J mice lacked a unique innate immune population, the natural killer dendritic cell (NKDC), which was shown to play a critical role in early CNS virus clearance via its ability to both present virus antigen to T cells and to lyse target cells.Emily M. L. ChastainDaniel R. GettsStephen D. MillerAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 4 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Emily M. L. Chastain Daniel R. Getts Stephen D. Miller Deficient Natural Killer Dendritic Cell Responses Underlay the Induction of Theiler's Virus-Induced Autoimmunity
description	ABSTRACT The initiating events in autoimmune disease remain to be completely understood, but it is thought that genetic predisposition synergizes with “environmental” factors, including viral infection, leading to disease. One elegant animal model used to study the pathogenesis of multiple sclerosis that perfectly blends genetics and environmental components in the context of virus-induced autoimmunity is Theiler's murine encephalitis virus-induced demyelinating disease (TMEV-IDD). TMEV-infected disease-susceptible SJL/J mice develop a persistent central nervous system (CNS) infection and later develop autoimmune demyelination, while disease-resistant C57BL/6 (B6) mice rapidly clear the infection and develop no autoimmune pathology. Mice of the (B6 × SJL/J)F1 cross between these two mouse strains are classified as intermediately susceptible. We employed this model to investigate if rapid virus clearance in B6 versus SJL/J mice was perhaps related to differences in the innate immune response in the CNS of the two strains in the first few days following intracerebral virus inoculation. Here we show that SJL/J mice lack, in addition to NK cells, a novel innate immune subset known as natural killer dendritic cells (NKDCs), which express phenotypic markers (CD11cint NK1.1+) and functional activity of both NK cells and DCs. These NKDCs are activated in the periphery and migrate into the infected CNS in a very late antigen 4 (VLA-4)-dependent fashion. Most significantly, NKDCs are critical for CNS clearance of TMEV, as transfer of NKDCs purified from B6 mice into TMEV-IDD-susceptible (B6 × SJL/J)F1 mice promotes viral clearance. Together the findings of this work show for the first time a link between NKDCs, viral infection, and CNS autoimmunity. IMPORTANCE 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. Induction of TMEV-IDD is genetically controlled as SJL/J mice develop persistent central nervous system (CNS) infection leading to chronic autoimmune demyelination, while C57BL/6 mice rapidly clear virus and are disease resistant. We determined that, as opposed to resistant B6 mice, disease-susceptible SJL/J mice lacked a unique innate immune population, the natural killer dendritic cell (NKDC), which was shown to play a critical role in early CNS virus clearance via its ability to both present virus antigen to T cells and to lyse target cells.
format	article
author	Emily M. L. Chastain Daniel R. Getts Stephen D. Miller
author_facet	Emily M. L. Chastain Daniel R. Getts Stephen D. Miller
author_sort	Emily M. L. Chastain
title	Deficient Natural Killer Dendritic Cell Responses Underlay the Induction of Theiler's Virus-Induced Autoimmunity
title_short	Deficient Natural Killer Dendritic Cell Responses Underlay the Induction of Theiler's Virus-Induced Autoimmunity
title_full	Deficient Natural Killer Dendritic Cell Responses Underlay the Induction of Theiler's Virus-Induced Autoimmunity
title_fullStr	Deficient Natural Killer Dendritic Cell Responses Underlay the Induction of Theiler's Virus-Induced Autoimmunity
title_full_unstemmed	Deficient Natural Killer Dendritic Cell Responses Underlay the Induction of Theiler's Virus-Induced Autoimmunity
title_sort	deficient natural killer dendritic cell responses underlay the induction of theiler's virus-induced autoimmunity
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/cab09de284014cf6b9139d177615e0ee
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Deficient Natural Killer Dendritic Cell Responses Underlay the Induction of Theiler's Virus-Induced Autoimmunity

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