Cutting Edge: Multiple Sclerosis-Like Lesions Induced by Effector CD8 T Cells Recognizing a Sequestered Antigen on Oligodendrocytes

Saxena, Amit; Bauer, Jan; Scheikl, Tanja; Zappulla, Jacques; Audebert, Marc; Desbois, Sabine; Waisman, Ari; Lassmann, Hans; Liblau, Roland; Mars, Lennart T.

doi:10.4049/jimmunol.181.3.1617

Cited by 126 publications

(111 citation statements)

References 18 publications

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“…To this end, the Rosa26 tm(HA)1Lib mice (20) were crossed with the Orex-Cre animals, expressing Cre under the control of the human orexin promoter (21).…”

Section: Resultsmentioning

confidence: 99%

“…The (BALB/cJ × C57BL/6J) F1-Orex-HA mice were generated by crossing the BALB/cJ-Rosa26 tm(HA)1Lib mice (20) with the C57BL/6J Orex-Cre mice, a gift from T. Sakurai, Kanazawa University, Kanazawa, Japan (21). In the resulting double-transgenic Orex-HA mice, the expression of HA of an H1N1 influenza virus, which is otherwise prevented by an upstream floxed Stop cassette, was induced because of the expression of the Cre recombinase specifically in orexin + neurons.…”

Section: Methodsmentioning

confidence: 99%

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CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Bernard‐Valnet

Yshii

Quériault

et al. 2016

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

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120

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Narcolepsy with cataplexy is a rare and severe sleep disorder caused by the destruction of orexinergic neurons in the lateral hypothalamus. The genetic and environmental factors associated with narcolepsy, together with serologic data, collectively point to an autoimmune origin. The current animal models of narcolepsy, based on either disruption of the orexinergic neurotransmission or neurons, do not allow study of the potential autoimmune etiology. Here, we sought to generate a mouse model that allows deciphering of the immune mechanisms leading to orexin + neuron loss and narcolepsy development. We generated mice expressing the hemagglutinin (HA) as a "neo-self-antigen" specifically in hypothalamic orexin + neurons (called Orex-HA), which were transferred with effector neo-self-antigen-specific T cells to assess whether an autoimmune process could be at play in narcolepsy. Given the tight association of narcolepsy with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, we first tested the pathogenic contribution of CD4 Th1 cells. Although these T cells readily infiltrated the hypothalamus and triggered local inflammation, they did not elicit the loss of orexin + neurons or clinical manifestations of narcolepsy. In contrast, the transfer of cytotoxic CD8 T cells (CTLs) led to both T-cell infiltration and specific destruction of orexin + neurons. This phenotype was further aggravated upon repeated injections of CTLs. In situ, CTLs interacted directly with MHC class I-expressing orexin + neurons, resulting in cytolytic granule polarization toward neurons. Finally, drastic neuronal loss caused manifestations mimicking human narcolepsy, such as cataplexy and sleep attacks. This work demonstrates the potential role of CTLs as final effectors of the immunopathological process in narcolepsy.arcolepsy with cataplexy, referred to as type 1 narcolepsy (T1N), is a rare and chronic neurological disease characterized by excessive daytime sleepiness, sudden loss of muscle tone triggered by emotions (cataplexy), sleep paralysis, hypnagogic hallucinations, and fragmented nocturnal sleep (1). T1N is caused by a defective neurotransmission by the orexin/hypocretin neuropeptide and is associated with a selective and almost complete loss (85-100%) of orexinergic neurons in the hypothalamus (2, 3). The mechanisms leading to this neuronal loss are not yet elucidated, although current evidence points to an autoimmune process. Indeed, T1N is tightly associated with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, carried by 98.4% of patients vs. 17.7% of the general European population (4). An independent association with HLA class I alleles was recently revealed in two independent studies (5, 6). Additionally, an association with polymorphisms in the T-cell receptor (TCR) α chain locus was found and replicated (7,8). Moreover, autoantibodies recognizing different antigenic targets expressed in the central nervous system (CNS) have been identified in the serum and cerebrospinal fluid (CSF) of narcoleptic patients (9-11)....

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“…To this end, the Rosa26 tm(HA)1Lib mice (20) were crossed with the Orex-Cre animals, expressing Cre under the control of the human orexin promoter (21).…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Bernard‐Valnet

Yshii

Quériault

et al. 2016

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

Self Cite

120

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“…The adoptive transfer of HA-specific Tc1 cells in MOG-HA mice induces inflammatory lesions in the optic nerve, spinal cord, and brain. These lesions associate CD8 T cell infiltration with focal loss of oligodendrocytes, demyelination, axonal damage, and microglia activation, features that are very reminiscent of active MS lesions [62]. A similar transgenic model introduced ovalbumin (OVA) under the proximal MBP promoter (ODC-OVA mice) to induce the expression of a neo-self antigen in the cytosol of oligodendrocytes.…”

Section: Cd8 T Cells In Animal Models Of Msmentioning

confidence: 99%

Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

et al. 2011

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a b s t r a c tMultiple sclerosis (MS) is an immune-mediated disease of the central nervous system leading to demyelination and axonal/neuronal loss. Cumulating evidence points to a key role for CD8 T cells in this disabling disease. Oligoclonal CD8 T cells reside in demyelinating plaques where they are likely to contribute to tissue destruction. Histopathological analyses and compelling observations from animal models indicate that cytotoxic CD8 T cells target neural cell populations with the potential of causing lesions reminiscent of MS. However, CD8 T cell differentiation results in several subsets of effector CD8 T cells that could be differentially implicated in the mechanisms contributing to tissue damage. Moreover CD8 regulatory T cells arise as important populations involved in restoring immune homoeostasis and in maintaining immune privileged sites. Here we examine the current literature pertaining to the role of CD8 effector and regulatory T cell subsets in the pathogenesis of MS.

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“…Injection of susceptible mouse strains (SJL, PL/J) with myelin oligodendrocytes glycoprotein, MBP or proteolipid protein (PLP)-derived MHC class II-restricted peptides in combination with CFA and/or pertussis toxin, results in CD4 1 T-cell infiltration and demyelinating disease in the EAE rodent model for MS. Although most experimental data are based on CD4 1 T cells, it was shown that adoptive transfer of MBP-specific CD8 1 T cells resulted in severe neurological symptoms and weight loss [14] and that adoptive transfer of a supra-physiological number of pre-activated, specific CD8 1 T cells into transgenic mice expressing influenza hemagglutinin in oligodendrocytes led to inflammatory lesions in the CNS [15]. Given that steady state DC induce and maintain peripheral T-cell tolerance to self [4][5][6][7], it is surprising that injection of selfantigens together with CFA readily induces autoimmunity in laboratory animals, suggesting that auto-reactive T cells persist in the repertoire.…”

Section: Cd8mentioning

confidence: 99%

Antigens expressed by myelinating glia cells induce peripheral cross‐tolerance of endogenous CD8⁺ T cells

Schildknecht

Probst

McCoy³

et al. 2009

Eur J Immunol

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Auto-reactivity of T cells is largely prevented by central and peripheral tolerance. Nevertheless, immunization with certain self-antigens emulsified in CFA induces autoimmunity in rodents, suggesting that tolerance to some self-antigens is not robust. To investigate the fate of nervous system-specific CD8 1 T cells, which only recently came up as being important contributors for MS pathogenesis, we developed a mouse model that allows inducible expression of lymphocytic choriomeningitis virus-derived CD8 1 T-cell epitopes specifically in oligodendrocytes and Schwann cells, the myelinating glia of the nervous system. These transgenic CD8 1 T-cell epitopes induced robust tolerance of endogenous auto-reactive T cells, which proved thymus-independent and was mediated by crosspresenting bone-marrow-derived cells. Immunohistological staining of secondary lymphoid organs demonstrated the presence of glia-derived antigens in DC, suggesting that peripheral tolerance of CD8 1 T cells results from uptake and presentation by steady state DC.

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Cutting Edge: Multiple Sclerosis-Like Lesions Induced by Effector CD8 T Cells Recognizing a Sequestered Antigen on Oligodendrocytes

Cited by 126 publications

References 18 publications

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

Antigens expressed by myelinating glia cells induce peripheral cross‐tolerance of endogenous CD8⁺ T cells

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Cutting Edge: Multiple Sclerosis-Like Lesions Induced by Effector CD8 T Cells Recognizing a Sequestered Antigen on Oligodendrocytes

Cited by 126 publications

References 18 publications

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

Antigens expressed by myelinating glia cells induce peripheral cross‐tolerance of endogenous CD8+ T cells

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Antigens expressed by myelinating glia cells induce peripheral cross‐tolerance of endogenous CD8⁺ T cells