Endogenous presentation of self myelin epitopes by CNS-resident APCs in Theiler’s virus–infected mice

Katz-Levy, Yael; Neville, Katherine L.; Girvin, Ann M.; Vanderlugt, Carol L.; Pope, Jonathan G.; Tan, Litjen; Miller, Stephen D.

doi:10.1172/jci7292

Cited by 132 publications

(133 citation statements)

References 76 publications

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“…TMEV-induced demyelinating disease has been shown to be associated with an autoimmune CD4 ϩ T cell response directed against immunodominant myelin Ag, PLP 139 -151 (12,13). As the demyelinating disease progresses, epitope spreading gives rise to CD4 ϩ T cell responses against multiple additional encephalitogenic myelin epitopes in an ordered progression, PLP 56 -70 , myelin oligodendrocyte glycoprotein [92][93][94][95][96][97][98][99][100][101][102][103][104][105][106] , PLP 178 -191 , and myelin basic protein 84 -104 (14,15). The innate immune response initiates the immune response to TMEV and influences the development of the adaptive immune response.…”

Section: Ultiple Sclerosis (Ms)mentioning

confidence: 99%

Innate Immune CD11b+Gr-1+ Cells, Suppressor Cells, Affect the Immune Response during Theiler’s Virus-Induced Demyelinating Disease

Bowen

Olson

2009

The Journal of Immunology

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Multiple sclerosis is a demyelinating disease associated with an inflammatory immune response in the CNS. Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease is a relevant mouse model for the study of multiple sclerosis. TMEV infection of susceptible mice leads to a persistent virus infection of the CNS which contributes to development of demyelinating disease. We have previously shown that the innate immune response can affect the development and progression of demyelinating disease. In the current studies, we determined that the predominant infiltrating cells during the innate immune response are CD11b+Ly6C+ cells. CD11b+Ly6C+ cells are immature myeloid cells that have exited the bone marrow without maturing and have been shown to suppress CD4+ and CD8+ T cell responses. Therefore, we wanted to determine what role these cells play in development and progression of demyelinating disease. TMEV-infected mice depleted of CD11b+Ly6C+ cells during the innate immune response developed a reduced demyelinating disease which was associated with a decreased myelin-specific CD4+ T cell response and a decreased inflammatory immune response in the CNS. TMEV-infected mice depleted of CD11b+Ly6C+ cells had increased virus-specific CD4+ and CD8+ T cell responses during early virus infection associated with increased expression of IFN-γ and IL-17 and decreased expression of IL-10 in the CNS. These results suggest that CD11b+Ly6C+ cells which infiltrate into the CNS during the innate immune response are myeloid-derived suppressor cells that suppress virus-specific T cell responses and contribute to the development of demyelinating disease.

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Section: Ultiple Sclerosis (Ms)mentioning

confidence: 99%

Innate Immune CD11b+Gr-1+ Cells, Suppressor Cells, Affect the Immune Response during Theiler’s Virus-Induced Demyelinating Disease

Bowen

Olson

2009

The Journal of Immunology

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“…To examine the antigen-presenting potential of phagocytes in EAE lesions, we isolated APCs from EAE spinal cords 2 h after i.v. infusion of OVA or saline by using gradient centrifugation (14). The cells were irradiated and cultured together with T OVA-GFP cells as ovalbumin-specific reporter cells.…”

Section: Uptake and Presentation Of Exogenous Antigen By Apcs Within Thementioning

confidence: 99%

Blood-borne soluble protein antigen intensifies T cell activation in autoimmune CNS lesions and exacerbates clinical disease

Odoardi

Kawakami

Klinkert

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…These events have been extensively examined, mainly in the case of the central nervous system (CNS) autoreactivity, where activated myelin antigen-specific T cells migrate to the CNS, leading to autoimmune encephalomyelitis (1). Flow of specific and nonspecific T cells into the capillaries of the cerebral vasculature and adherence to endothelial cells has been shown, particularly after inflammation (2)(3)(4). The retention of the circulating autoreactive T cells that allows the passage across the blood-brain barrier depends on the presence of class II MHC bearing APC within the perivascular or Virchow-Robin space (5,6).…”

mentioning

confidence: 99%

Entry of diabetogenic T cells into islets induces changes that lead to amplification of the cellular response

Calderon

Carrero

Miller

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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In an accompanying paper, we find specific localization of diabetogenic T cells only to islets of Langerhans bearing the specific antigen. Instrumental in the specific localization was the presence of intraislet dendritic cells bearing the β-cell-peptide-MHC complex. Here, we report that the entry of diabetogenic CD4 T cells very rapidly triggered inflammatory gene expression changes in islets and vessels by up-regulating chemokines and adhesion molecules. Vascular cell adhesion molecule-1 (VCAM-1) expression was notable in blood vessels, as was intercellular adhesion molecule-1 (ICAM-1). ICAM-1 was also found on β-cells. These expression changes induced the entry of nonspecific T cells that otherwise did not localize to the islets. In contrast to the entry of diabetogenic CD4 T cells, the entrance of nonspecific T cells required a chemokine response and VCAM-1 expression by the islets. IFN-γ was important for the early gene expression changes in the islets. By microarray analysis, we detected up-regulation of a group of IFNinducible genes as early as 8 h post-T-cell transfer. These studies establish that entry of diabetogenic T cells induces a state of receptivity of islets to subsequent immunological insults.T-cell migration | autoimmunity | type 1 diabetes T he entry of T cells to tissues containing antigen-presenting cells (APCs) bearing their protein antigen leads to an inflammatory response. Within a few days, specific cells are difficult to distinguish among the many inflammatory cells made up of various leukocytes: macrophages, dendritic cells (DC), natural killer cells, and neutrophils. These events have been extensively examined, mainly in the case of the central nervous system (CNS) autoreactivity, where activated myelin antigen-specific T cells migrate to the CNS, leading to autoimmune encephalomyelitis (1). Flow of specific and nonspecific T cells into the capillaries of the cerebral vasculature and adherence to endothelial cells has been shown, particularly after inflammation (2-4). The retention of the circulating autoreactive T cells that allows the passage across the blood-brain barrier depends on the presence of class II MHC bearing APC within the perivascular or Virchow-Robin space (5, 6). After specific T cells are in play, they dictate the migration of nonspecific T cells into the CNS (4, 6, 7). Moreover, a random nonspecific entry and exit of T cells has been described in the mouse and rat (4,(8)(9)(10).In the case of autoimmune diabetes, activated diabetogenic CD4 T cells localized only to islets bearing their cognate antigen; thus, in mice bearing hen-egg white lysozyme (HEL) under the insulin promoter (IP-HEL), T cells bearing a transgenic T-cell receptor for HEL peptides only localized to islets bearing HEL. The same was true for the localization of diabetogenic T cells in the NOD model of spontaneous diabetes (11). In both cases, the intraislet DCs were instrumental in the presentation of the peptide-MHC complexes and in the localization of the CD4 T cells. We did not obtain evidence t...

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Endogenous presentation of self myelin epitopes by CNS-resident APCs in Theiler’s virus–infected mice

Cited by 132 publications

References 76 publications

Innate Immune CD11b+Gr-1+ Cells, Suppressor Cells, Affect the Immune Response during Theiler’s Virus-Induced Demyelinating Disease

Innate Immune CD11b+Gr-1+ Cells, Suppressor Cells, Affect the Immune Response during Theiler’s Virus-Induced Demyelinating Disease

Blood-borne soluble protein antigen intensifies T cell activation in autoimmune CNS lesions and exacerbates clinical disease

Entry of diabetogenic T cells into islets induces changes that lead to amplification of the cellular response

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