Unravelling the T‐cell‐mediated autoimmune attack on CNS myelin in a new primate EAE model induced with MOG_34–56 peptide in incomplete adjuvant

Abstract

Induction of experimental autoimmune encephalomyelitis (EAE) has been documented in common marmosets using peptide 34-56 from human myelin/oligodendrocyte glycoprotein ) in incomplete Freund's adjuvant (IFA). Here, we report that this EAE model is associated with widespread demyelination of grey and white matter. We performed an in-depth analysis of the specificity, MHC restriction and functions of the activated T cells in the model, which likely cause EAE in an autoantibody-independent manner. T-cell lines isolated from blood and lymphoid organs of animals immunized with MOG 34-56 displayed high production of IL-17A and specific lysis of MOG 34-56 -pulsed EBV B-lymphoblastoid cells as typical hallmarks. Cytotoxicity was directed at the epitope MOG [40][41][42][43][44][45][46][47][48] presented by the non-classical MHC class Ib allele Caja-E, which is orthologue to HLA-E and is expressed in non-inflamed brain. In vivo activated T cells identified by flow cytometry in cultures with MOG 34-56, CD561 T cells also expressed CD27, but CD16, CD45RO, CD28 and CCR7 were absent. These results show that, in the MOG34-56/IFA marmoset EAE model, a Caja-E-restricted population of autoreactive cytotoxic T cells plays a key role in the process of demyelination in the grey and white matter.Key words: Common marmoset . Cytotoxicity . HLA-E . Oligodendrocytes . Natural killer-cytotoxic T lymphocyte (NK-CTL)Supporting Information available online IntroductionMultiple sclerosis (MS) is a chronic inflammatory disease of the human central nervous system (CNS) of unknown aetiology. The pathological hallmark of MS is the lesion. Lesions are regions of usually focal demyelination of variable size localized in the grey and/or white matter of the brain and spinal cord, formed by a combined cellular and humoral autoimmune attack. CNS-targeting autoimmune reactions are thought to be induced as a response to infection (response-to-infection paradigm) [1], although the pathogen(s) that elicit this pathogenic process in MS has not been identified. We have proposed a responseto-damage paradigm for MS, based on the work in a unique nonhuman primate model of MS, experimental autoimmune encephalomyelitis (EAE) in common marmosets (Callithrix jacchus), [2]. The new concept postulates that autoimmunity in MS patients is caused by a genetically predisposed hyper-response to myelin antigens released from damaged white matter due to an unknown antecedent event. We showed that the most important anti-myelin reactivity for the induction of neurological deficit is mediated by antigen-experienced T-cells specific for peptides 34-56 of myelin/oligodendrocyte glycoprotein ) [3].Subsequently it was demonstrated that these cells could be activated in vivo by immunization of marmosets with MOG in incomplete Freund's adjuvant (IFA) [4]. A peptide in IFA emulsion is a more common formulation for the in vivo activation of antigen-experienced T-cells than for autoreactive T-cells as bacterial ligands of innate antigen receptors are usually required. It is no...

Selective Blockade of CD28-Mediated T Cell Costimulation Protects Rhesus Monkeys against Acute Fatal Experimental Autoimmune Encephalomyelitis

“…Data obtained in an equivalent nonhuman primate EAE model, the rhMOG-induced model in marmosets, show that the core pathogenic T cells are derived from effector memory cells present in the natural repertoire (32). Thus, we tested cellular and humoral immune responses against rhMOG to determine whether blockade of T cell costimulation via CD28 with FR104 might affect the generation of pathogenic cells.…”

Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein

“…This implies that LCV-infected B cells suppress the activation of naive T cells; however, the constitutively expressed CD70 molecules on mouse DCs relay strong in vivo activation signals to T cells via homodimeric CD27 receptors (50). We reported previously that CD27 is expressed by autoaggressive MOG34-56-specific CTLs induced in the marmoset EAE model (9). Ligand binding to CD27 complements CD28 in determining the size of CD8 + effector memory T cell populations (51).…”

“…+ CTLs (7)(8)(9). Intriguingly, when marmosets were immunized with recombinant human MOG (rhMOG), representing the full-length extracellular domain , formulated with IFA, we observed only T cell activation against the MOG24-36 epitope (10).…”

The common marmoset (<i>Callithrix jacchus</i>): a relevant preclinical model of human (auto)immune-mediated inflammatory disease of the brain

“…We further characterized these late-appearing T cells in marmosets immunized with peptide MOG34-56 formulated with IFA, in which clinical signs and widespread demyelination of white and grey matter developed without the induction of myelin-binding autoantibodies (Jagessar et al, 2010). It was shown that the T cells are specific for the MOG40-48 epitope, which is presented via MHC class I/Caja-E molecules; that the responding T cells have an NK-CTL (natural killer-cytotoxic T lymphocyte) phenotype (CD3 + CD8 + CD56 +); and that they display cytotoxic activity against EBV-infected B cells pulsed with MOG34-56 (Jagessar et al, 2012a). This type of T cells has been found in humans in the repertoire of effector memory T cells that keep chronic latent infection with CMV under control (Pietra et al, 2003).…”

“…NK-CTLs against the MOG epitope 40-48 seem to play an important role in late-stage disease. These T cells can be induced by immunization of marmosets with MOG peptide 34-56 in IFA (Jagessar et al, 2012a), a condition where myelinbinding antibodies are not formed (Jagessar et al, 2015). The pathogenic role of these cytotoxic cells in MS is not exactly clear.…”