Limited sufficiency of antigen presentation by dendritic cells in models of central nervous system autoimmunity

Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19004, USA.
Journal of Autoimmunity (Impact Factor: 8.41). 02/2011; 36(1):56-64. DOI: 10.1016/j.jaut.2010.10.006
Source: PubMed


Experimental autoimmune encephalomyelitis (EAE), a model for the human disease multiple sclerosis (MS), is dependent upon the activation and effector functions of autoreactive CD4 T cells. Multiple interactions between CD4 T cells and major histocompatibility class II (MHCII)+ antigen presenting cells (APCs) must occur in both the periphery and central nervous system (CNS) to elicit autoimmunity. The identity of the MHCII+ APCs involved throughout this process remains in question. We investigated which APC in the periphery and CNS mediates disease using transgenic mice with MHCII expression restricted to dendritic cells (DCs). MHCII expression restricted to DCs results in normal susceptibility to peptide-mediated EAE. Indeed, radiation-sensitive bone marrow-derived DCs were sufficient for all APC functions during peptide-induced disease. However, DCs alone were inefficient at promoting disease after immunization with the myelin protein myelin oligodendrocyte glycoprotein (MOG), even in the presence of MHCII-deficient B cells. Consistent with a defect in disease induction following protein immunization, antigen presentation by DCs alone was incapable of mediating spontaneous optic neuritis. These results indicate that DCs are capable of perpetuating CNS-targeted autoimmunity when antigens are readily available, but other APCs are required to efficiently initiate pathogenic cognate CD4 T cell responses.

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Available from: Robert J Mikesell, Sep 30, 2015
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    • "Thymic transplants were performed as previously described (Wu et al., 2011). "
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    ABSTRACT: Regulatory T cells (Tregs) are CD4(+) T cells that maintain immune homeostasis and prevent autoimmunity. Like all CD4(+) T cells, Tregs require antigen-specific signals via T cell receptor-major histocompatibility complex class II (TCR-MHCII) interactions for their development. However, the requirement for MHCII in Treg homeostasis in tissues such as intestinal lamina propria (LP) is unknown. We examined LP Treg homeostasis in a transgenic mouse model that lacks peripheral TCR-MHCII interactions and generation of extrathymic Tregs (iTregs). Thymically generated Tregs entered the LP of weanlings and proliferated independently of MHCII to fill the compartment. The adult LP was a closed niche; new thymic Tregs were excluded, and Tregs in parabiotic pairs were LP resident. The isolated LP niche was interleukin-2 (IL-2) independent but dependent on commensal bacteria. Thus, an LP Treg niche can be filled, isolated, and maintained independently of antigen signals and iTregs. This niche may represent a tissue-specific mechanism for maintaining immune tolerance. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 12/2014; 9(5). DOI:10.1016/j.celrep.2014.11.006 · 8.36 Impact Factor
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    • "For the combined analysis of three different experiments (n ¼ 7e8 mice/experiment), the clinical scores were normalized to the maximum disease score observed in each experiment and represented as % maximal disease score. Ex vivo quantification of antigen-specific, IFN-g and IL-17-producing CD4 þ T cells was performed as described previously [22]. Briefly, draining lymph nodes were isolated from mice and re-stimulated with MOG peptide or media alone for 18 h. "
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    ABSTRACT: Strategies to expand regulatory T cells hold therapeutic potential for ameliorating T cell-mediated autoimmunity. Recently, we reported that the requirements for T cell receptor signaling in conventional T cell and regulatory T cell proliferation are different. Using mutant mice that display defective T cell receptor-mediated phospholipase Cγ (PLCγ) activation, we hereby demonstrate that PLCγ activation is required for antigen-specific conventional T cell proliferation but not for IL-2-induced regulatory T cell proliferation. This led us to hypothesize that in conjunction with IL-2, pharmacological inhibition of T cell receptor-mediated PLCγ activation might offer a novel therapeutic strategy to expand regulatory T cells while simultaneously inhibiting conventional T cell proliferation. Indeed, using the calcineurin inhibitor Cyclosporine A to inhibit signaling downstream of PLCγ, we found that Cyclosporine A attenuated antigen-specific Tconv proliferation but permitted IL-2-induced regulatory T cell expansion in vitro and in vivo. Furthermore, the combination of Cyclosporine A and IL-2 was superior over either Cyclosporine A or IL-2 monotherapy in protection against the T cell-mediated demyelinating autoimmune disease mouse model, experimental autoimmune encephalomyelitis. Thus, a combination of TCR signaling inhibition and IL-2 might be a beneficial strategy in expanding regulatory T cells and inhibiting conventional T cell proliferation in autoimmune settings.
    Journal of Autoimmunity 07/2013; 44. DOI:10.1016/j.jaut.2013.06.009 · 8.41 Impact Factor
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    • "EAE was induced by immunization with 100 µg of rhMOG or 100 µg of MOG35-55 peptide emulsified 1∶1 in Complete Freund's Adjuvant (Sigma) containing 4 mg/ml of Mycobateria tuberculosis (H37RA) (Difco). The amount of rhMOG was pre-determined based on earlier reports [35], [45]. Mice also received two intra-peritoneal doses of pertussis toxin (200 ng) (List biological laboratories Inc.) the day of immunization and 48 h later. "
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    ABSTRACT: Clinical studies of B cell depletion in Multiple Sclerosis (MS) have revealed that B Lymphocytes are involved in the neuro-inflammatory process, yet it remains unclear how B cells can exert pro- and anti-inflammatory functions during MS. Experimental Autoimmune Encephalomyelitis (EAE) is an animal model of MS whereby myelin-specific T cells become activated and subsequently migrate to the Central Nervous System (CNS) where they perform pro-inflammatory functions such as cytokine secretion. Typically EAE is induced by immunization of mice of a susceptible genetic background with peptide antigen emulsified in Complete Freund's Adjuvant. However, novel roles for B-lymphocytes in EAE may also be explored by immunization with full-length myelin oligodendrocyte glycoprotein (MOG) that contains the B cell conformational epitope. Here we show that full length MOG immunization promotes a chronic disease in mice that depends on antigen-driven secondary diversification of the B cell receptor. Activation-Induced Deaminase (AID) is an enzyme that is essential for antigen-driven secondary diversification of the B cell receptor. We immunized AID(-/-) mice with the extracellular domain (amino acids 1-120) of recombinant human MOG protein (rhMOG) and examined the incidence and severity of disease in AID(-/-) versus wild type mice. Corresponding with these clinical measurements, we also evaluated parameters of T cell activation in the periphery and the CNS as well as the generation of anti-MOG antibodies (Ab). AID(-/-) mice exhibit reduced severity and incidence of EAE. This suggests that the secondary diversification of the B cell receptor is required for B cells to exert their full encephalogenic potential during rhMOG-induced EAE, and possibly also during MS.
    PLoS ONE 04/2013; 8(4):e61478. DOI:10.1371/journal.pone.0061478 · 3.23 Impact Factor
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