The Activation Status of Neuroantigen-specific T Cells in the Target Organ Determines the Clinical Outcome of Autoimmune Encephalomyelitis

Kawakami, Naoto; Laßmann, Silke; Li, Zhaoxia; Odoardi, Francesca; Ritter, Thomas; Ziemssen, Tjalf; Klinkert, Wolfgang E. F.; Ellwart, Joachim W.; Bradl, Monika; Krivacic, Kimberly; Lassmann, H.; Ransohoff, Richard M.; Volk, Hans‐Dieter; Wekerle, Hartmut; Linington, Christopher; Flügel, Alexander

doi:10.1084/jem.20031064

Cited by 172 publications

(150 citation statements)

References 55 publications

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“…Clinical EAE generally correlates with the number and activation status of CNS-infiltrating effector CD4 ϩ T cells and inversely with regulatory T cell (Treg) numbers (17). We found that pDC depletion did not significantly affect the numbers of CNS CD4 ϩ T cells and Foxp3 ϩ CD4 ϩ Tregs (p ϭ 0.2; Fig.…”

Section: Pdcs Modulate the Activation And Frequency Of Th1 And Th17 Cmentioning

confidence: 69%

Cutting Edge: Central Nervous System Plasmacytoid Dendritic Cells Regulate the Severity of Relapsing Experimental Autoimmune Encephalomyelitis

Bailey-Bucktrout

Caulkins

Goings

et al. 2008

The Journal of Immunology

132

126

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Plasmacytoid dendritic cells (pDCs) have both stimulatory and regulatory effects on T cells. pDCs are a major CNS-infiltrating dendritic cell population during experimental autoimmune encephalomyelitis but, unlike myeloid dendritic cells, have a minor role in T cell activation and epitope spreading. We show that depletion of pDCs during either the acute or relapse phases of experimental autoimmune encephalomyelitis resulted in exacerbation of disease severity. pDC depletion significantly enhanced CNS but not peripheral CD4+ T cell activation, as well as IL-17 and IFN-γ production. Moreover, CNS pDCs suppressed CNS myeloid dendritic cell-driven production of IL-17, IFN-γ, and IL-10 in an IDO-independent manner. The data demonstrate that pDCs play a critical regulatory role in negatively regulating pathogenic CNS CD4+ T cell responses, highlighting a new role for pDCs in inflammatory autoimmune disease.

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Section: Pdcs Modulate the Activation And Frequency Of Th1 And Th17 Cmentioning

confidence: 69%

Cutting Edge: Central Nervous System Plasmacytoid Dendritic Cells Regulate the Severity of Relapsing Experimental Autoimmune Encephalomyelitis

Bailey-Bucktrout

Caulkins

Goings

et al. 2008

The Journal of Immunology

132

126

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“…In fact, we previously reported that APCs freshly isolated from naive leptomeninges present low doses of incorporated MBP to specific T cells. In addition, the infusion of myelin protein into the leptomeningeal space converted lowencephalitogenic T cells to high-encephalitogenic T cells (30).…”

Section: Discussionmentioning

confidence: 99%

Visualizing context-dependent calcium signaling in encephalitogenic T cells in vivo by two-photon microscopy

Kyratsous

Bauer

Zhang

et al. 2017

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

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In experimental autoimmune encephalitis (EAE), autoimmune T cells are activated in the periphery before they home to the CNS. On their way, the T cells pass through a series of different cellular milieus where they receive signals that instruct them to invade their target tissues. These signals involve interaction with the surrounding stroma cells, in the presence or absence of autoantigens. To portray the serial signaling events, we studied a T-cell-mediated model of EAE combining in vivo two-photon microscopy with two different activation reporters, the FRET-based calcium biosensor Twitch1 and fluorescent NFAT. In vitro activated T cells first settle in secondary (2°) lymphatic tissues (e.g., the spleen) where, in the absence of autoantigen, they establish transient contacts with stroma cells as indicated by sporadic short-lived calcium spikes. The T cells then exit the spleen for the CNS where they first roll and crawl along the luminal surface of leptomeningeal vessels without showing calcium activity. Having crossed the blood-brain barrier, the T cells scan the leptomeningeal space for autoantigen-presenting cells (APCs). Sustained contacts result in long-lasting calcium activity and NFAT translocation, a measure of full T-cell activation. This process is sensitive to anti-MHC class II antibodies. Importantly, the capacity to activate T cells is not a general property of all leptomeningeal phagocytes, but varies between individual APCs. Our results identify distinct checkpoints of T-cell activation, controlling the capacity of myelin-specific T cells to invade and attack the CNS. These processes may be valuable therapeutic targets.autoimmunity | intracellular calcium | T-cell activation | central nervous system | two-photon imaging

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“…Cytofluorometric analysis was performed with FACS-Calibur operated by Cell Quest software (Becton Dickinson). Intracellular IFN␥ staining was performed as described (34). The antibodies used are listed in SI Materials and Methods.…”

Section: Methodsmentioning

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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The Activation Status of Neuroantigen-specific T Cells in the Target Organ Determines the Clinical Outcome of Autoimmune Encephalomyelitis

Cited by 172 publications

References 55 publications

Cutting Edge: Central Nervous System Plasmacytoid Dendritic Cells Regulate the Severity of Relapsing Experimental Autoimmune Encephalomyelitis

Cutting Edge: Central Nervous System Plasmacytoid Dendritic Cells Regulate the Severity of Relapsing Experimental Autoimmune Encephalomyelitis

Visualizing context-dependent calcium signaling in encephalitogenic T cells in vivo by two-photon microscopy

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

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