Roland S Liblau

University of Toulouse, Tolosa de Llenguadoc, Midi-Pyrénées, France

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Publications (144)1156.19 Total impact

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    ABSTRACT: Lymphatic endothelial cells (LECs) directly express peripheral tissue antigens and induce CD8 T-cell deletional tolerance. LECs express MHC-II molecules, suggesting they might also tolerize CD4 T cells. We demonstrate that when β-galactosidase (β-gal) is expressed in LECs, β-gal-specific CD8 T cells undergo deletion via the PD-1/PD-L1 and LAG-3/MHC-II pathways. In contrast, LECs do not present endogenous β-gal in the context of MHC-II molecules to β-gal-specific CD4 T cells. Lack of presentation is independent of antigen localization, as membrane-bound haemagglutinin and I-Eα are also not presented by MHC-II molecules. LECs express invariant chain and cathepsin L, but not H2-M, suggesting that they cannot load endogenous antigenic peptides onto MHC-II molecules. Importantly, LECs transfer β-gal to dendritic cells, which subsequently present it to induce CD4 T-cell anergy. Therefore, LECs serve as an antigen reservoir for CD4 T-cell tolerance, and MHC-II molecules on LECs are used to induce CD8 T-cell tolerance via LAG-3.
    Nature Communications 04/2015; 6:6771. DOI:10.1038/ncomms7771 · 10.74 Impact Factor
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    ABSTRACT: The discovery of hypocretins (orexins) and their causal implication in narcolepsy is the most important advance in sleep research and sleep medicine since the discovery of rapid eye movement sleep. Narcolepsy with cataplexy is caused by hypocretin deficiency owing to destruction of most of the hypocretin-producing neurons in the hypothalamus. Ablation of hypocretin or hypocretin receptors also leads to narcolepsy phenotypes in animal models. Although the exact mechanism of hypocretin deficiency is unknown, evidence from the past 20 years strongly favours an immune-mediated or autoimmune attack, targeting specifically hypocretin neurons in genetically predisposed individuals. These neurons form an extensive network of projections throughout the brain and show activity linked to motivational behaviours. The hypothesis that a targeted immune-mediated or autoimmune attack causes the specific degeneration of hypocretin neurons arose mainly through the discovery of genetic associations, first with the HLA-DQB1*06:02 allele and then with the T-cell receptor α locus. Guided by these genetic findings and now awaiting experimental testing are models of the possible immune mechanisms by which a specific and localised brain cell population could become targeted by T-cell subsets. Great hopes for the identification of new targets for therapeutic intervention in narcolepsy also reside in the development of patient-derived induced pluripotent stem cell systems. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Neurology 03/2015; 14(3):318-28. DOI:10.1016/S1474-4422(14)70218-2 · 21.82 Impact Factor
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    ABSTRACT: The discovery of hypocretins (orexins) and their causal implication in narcolepsy is the most important advance in sleep research and sleep medicine since the discovery of rapid eye movement sleep. Narcolepsy with cataplexy is caused by hypocretin defi ciency owing to destruction of most of the hypocretin-producing neurons in the hypothalamus. Ablation of hypocretin or hypocretin receptors also leads to narcolepsy phenotypes in animal models. Although the exact mechanism of hypocretin defi ciency is unknown, evidence from the past 20 years strongly favours an immune-mediated or autoimmune attack, targeting specifi cally hypocretin neurons in genetically predisposed individuals. These neurons form an extensive network of projections throughout the brain and show activity linked to motivational behaviours. The hypothesis that a targeted immune-mediated or autoimmune attack causes the specifi c degeneration of hypocretin neurons arose mainly through the discovery of genetic associations, fi rst with the HLA-DQB1*06:02 allele and then with the T-cell receptor α locus. Guided by these genetic fi ndings and now awaiting experimental testing are models of the possible immune mechanisms by which a specifi c and localised brain cell population could become targeted by T-cell subsets. Great hopes for the identifi cation of new targets for therapeutic intervention in narcolepsy also reside in the development of patient-derived induced pluripotent stem cell systems.
    The Lancet Neurology 03/2015; 14(14):318-28. DOI:10.1016/S1474-4422(14)70218-2. · 21.82 Impact Factor
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    ABSTRACT: Therapeutic strategies that modulate the deleterious immune response underlying progressive multifocal leukoencephalopathy-associated immune reconstitution inflammatory syndrome (PML-IRIS) are warranted [5]. Maraviroc, an antagonist of the CCR5 chemokine receptor that entered recently the HIV armamentarium, has been suggested to be beneficial in preventing or treating PML-IRIS [1, 4]. Since chemokine receptors play an important role in inflammatory cell migration, we investigated whether the molecular target of maraviroc is expressed on pathogenic T cells infiltrating PML-IRIS lesions. Paraffin-embedded brain specimens of inflammatory PML, obtained through diagnostic stereotactic brain biopsy, were analyzed from five previously described HIV-infected patients who developed PML-IRIS after initiation of antiretroviral therapy (ART) [3], and two non-HIV-infected patients who developed PML after chemotherapy or natalizumab, one who developed PML-IRIS, and the other at high risk of PML-IRIS ...
    Acta Neuropathologica 01/2015; 129(3). DOI:10.1007/s00401-015-1383-6 · 9.78 Impact Factor
  • Journal of Neuroimmunology 10/2014; 275(1-2). DOI:10.1016/j.jneuroim.2014.08.085 · 2.79 Impact Factor
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    ABSTRACT: Multiple sclerosis (MS), a demyelinating disease of the central nervous system (CNS), presents as a complex disease with variable clinical and pathological manifestations, involving different pathogenic pathways. Animal models, particularly experimental autoimmune encephalomyelitis (EAE), have been key to deciphering the pathophysiology of MS, although no single model can recapitulate the complexity and diversity of MS, or can, to date, integrate the diverse pathogenic pathways. Since the first EAE model was introduced decades ago, multiple classic (induced), spontaneous, and humanized EAE models have been developed, each recapitulating particular aspects of MS pathogenesis. The advances in technologies of genetic ablation and transgenesis in mice of C57BL/6J background and the development of myelin-oligodendrocyte glycoprotein (MOG)-induced EAE in C57BL/6J mice yielded several spontaneous and humanized EAE models, and resulted in a plethora of EAE models in which the role of specific genes or cell populations could be precisely interrogated, towards modeling specific pathways of MS pathogenesis/regulation in MS. Collectively, the numerous studies on the different EAE models contributed immensely to our basic understanding of cellular and molecular pathways in MS pathogenesis as well as to the development of therapeutic agents: several drugs available today as disease modifying treatments were developed from direct studies on EAE models, and many others were tested or validated in EAE. In this review, we discuss the contribution of major classic, spontaneous, and humanized EAE models to our understanding of MS pathophysiology and to insights leading to devising current and future therapies for this disease.
    Journal of Autoimmunity 08/2014; DOI:10.1016/j.jaut.2014.06.004 · 7.02 Impact Factor
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    ABSTRACT: The recognition of multiple ligands by a single TCR is an intrinsic feature of T cell biology, with important consequences for physiological and pathological processes. Polyspecific T cells targeting distinct self-antigens have been identified in healthy individuals as well as in the context of autoimmunity. We have previously shown that the 2D2 TCR recognizes the myelin oligodendrocyte glycoprotein epitope (MOG)35-55 as well as an epitope within the axonal protein neurofilament medium (NF-M15-35) in H-2(b) mice. In this study, we assess whether this cross-reactivity is a common feature of the MOG35-55-specific T cell response. To this end, we analyzed the CD4 T cell response of MOG35-55-immunized C57BL/6 mice for cross-reactivity with NF-M15-35. Using Ag recall responses, we established that an important proportion of MOG35-55-specific CD4 T cells also responded to NF-M15-35 in all mice tested. To study the clonality of this response, we analyzed 22 MOG35-55-specific T cell hybridomas expressing distinct TCR. Seven hybridomas were found to cross-react with NF-M15-35. Using an alanine scan of NF-M18-30 and an in silico predictive model, we dissected the molecular basis of cross-reactivity between MOG35-55 and NF-M15-35. We established that NF-M F24, R26, and V27 proved important TCR contacts. Strikingly, the identified TCR contacts are conserved within MOG38-50. Our data indicate that due to linear sequence homology, part of the MOG35-55-specific T cell repertoire of all C57BL/6 mice also recognizes NF-M15-35, with potential implications for CNS autoimmunity.
    The Journal of Immunology 08/2014; 193(7). DOI:10.4049/jimmunol.1400523 · 5.36 Impact Factor
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    ABSTRACT: Recent data suggest that oxidative injury may play an important role in demyelination and neurodegeneration in multiple sclerosis (MS). We compared the extent of oxidative injury in MS lesions with that in experimental models driven by different inflammatory mechanisms. It was only in a model of coronavirus-induced demyelinating encephalomyelitis that we detected an accumulation of oxidised phospholipids, which was comparable in extent to that in MS. In both, MS and coronavirus-induced encephalomyelitis, this was associated with massive microglial and macrophage activation, accompanied by the expression of the NADPH oxidase subunit p22phox but only sparse expression of inducible nitric oxide synthase (iNOS). Acute and chronic CD4+ T cell-mediated experimental autoimmune encephalomyelitis lesions showed transient expression of p22phox and iNOS associated with inflammation. Macrophages in chronic lesions of antibody-mediated demyelinating encephalomyelitis showed lysosomal activity but very little p22phox or iNOS expressions. Active inflammatory demyelinating lesions induced by CD8+ T cells or by innate immunity showed macrophage and microglial activation together with the expression of p22phox, but low or absent iNOS reactivity. We corroborated the differences between acute CD4+ T cell-mediated experimental autoimmune encephalomyelitis and acute MS lesions via gene expression studies. Furthermore, age-dependent iron accumulation and lesion-associated iron liberation, as occurring in the human brain, were only minor in rodent brains. Our study shows that oxidative injury and its triggering mechanisms diverge in different models of rodent central nervous system inflammation. The amplification of oxidative injury, which has been suggested in MS, is only reflected to a limited degree in the studied rodent models. Electronic supplementary material The online version of this article (doi:10.1007/s00401-014-1263-5) contains supplementary material, which is available to authorized users.
    Acta Neuropathologica 03/2014; 128(2). DOI:10.1007/s00401-014-1263-5 · 9.78 Impact Factor
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    ABSTRACT: Human T-cell lymphotropic virus (HTLV-1) is the causative agent of the incapacitating, neuroinflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Currently, there are no disease-modifying therapies with long-term clinical benefits or validated biomarkers for clinical follow-up in HAM/TSP. Although CD80 and CD86 costimulatory molecules play prominent roles in immune regulation and reflect disease status in multiple sclerosis (MS), data in HAM/TSP are lacking. Using flow cytometry, we quantified ex vivo and in vitro expression of CD80 and CD86 in PBMCs of healthy controls, HTLV-1-infected individuals with and without HAM/TSP, and MS patients. We hypothesized ex vivo CD80 and CD86 expressions and their in vitro regulation by interferon (IFN)-alpha/beta mirror similarities between HAM/TSP and MS and hence might reveal clinically useful biomarkers in HAM/TSP. Ex vivo expression of CD80 and CD86 in T and B cells increased in all HTLV-1 infected individuals, but with a selective defect for B cell CD86 upregulation in HAM/TSP. Despite decreased total B cells with increasing disease duration (p = 0.0003, r = -0.72), CD80+ B cells positively correlated with disease severity (p = 0.0017, r = 0.69) in HAM/TSP. B cell CD80 expression was higher in women with HAM/TSP, underscoring that immune markers can reflect the female predominance observed in most autoimmune diseases. In contrast to MS patients, CD80+ (p = 0.0001) and CD86+ (p = 0.0054) lymphocytes expanded upon in vitro culture in HAM/TSP patients. The expansion of CD80+ and CD86+ T cells but not B cells was associated with increased proliferation in HTLV-1 infection. In vitro treatment with IFN-beta but not IFN-alpha resulted in a pronounced increase of B cell CD86 expression in healthy controls, as well as in patients with neuroinflammatory disease (HAM/TSP and MS), similar to in vivo treatment in MS. We propose two novel biomarkers, ex vivo CD80+ B cells positively correlating to disease severity and CD86+ B cells preferentially induced by IFN-beta, which restores defective upregulation in HAM/TSP. This study suggests a role for B cells in HAM/TSP pathogenesis and opens avenues to B cell targeting (with proven clinical benefit in MS) in HAM/TSP but also CD80-directed immunotherapy, unprecedented in both HAM/TSP and MS.
    Journal of Neuroinflammation 01/2014; 11(1):18. DOI:10.1186/1742-2094-11-18 · 4.90 Impact Factor
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    ABSTRACT: Invariant NKT cells are innate lymphocytes with a broad tissue distribution. Here we demonstrate that iNKT cells reside in the central nervous system (CNS) in the absence of inflammation. Their presence in the CNS dramatically augments following inoculation of C57Bl/6 mice with the neurotropic Theiler's murine encephalomyelitis virus (TMEV). At the peak of inflammation the cellular infiltrate comprises 45 000 iNKT cells for 1 250 CD8 T cells specific for the immunodominant TMEV epitope. To study the interaction between these two T cell subsets, we infected both iNKT cell deficient Jα18(-/-) mice and iNKT cell enriched Vα14 transgenic mice with TMEV. The CD8 T cell response readily cleared TMEV infection in the iNKT cell deficient mice. However, in the iNKT cell enriched mice TMEV infection persisted and was associated with significant mortality. This was caused by the inhibition of the CD8 T cell response in the cervical lymph nodes and spleen after T cell priming. Taken together we demonstrate that iNKT cells reside in the CNS in the absence of inflammation and that their enrichment is associated with the inhibition of the anti-viral CD8 T cell response and an augmented mortality during acute encephalomyelitis.
    PLoS ONE 01/2014; 9(1):e87717. DOI:10.1371/journal.pone.0087717 · 3.53 Impact Factor
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    ABSTRACT: Paraneoplastic neurological disorders (PNDs) are syndromes that develop in cancer patients when an efficient antitumor immune response, directed against antigens expressed by both malignant cells and healthy neurons, damages the nervous system. Herein, we analyze existing data on the mechanisms of loss of self tolerance and nervous tissue damage that underpin one of the most frequent PNDs, the anti-Hu syndrome. In addition, we discuss future directions and propose potential strategies aimed at blocking deleterious encephalitogenic immune responses while preserving the antineoplastic potential of treatment.
    OncoImmunology 12/2013; 2(12):e27384. DOI:10.4161/onci.27384 · 6.28 Impact Factor
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    ABSTRACT: IMPORTANCE Idiopathic narcolepsy with cataplexy is thought to be an autoimmune disorder targeting hypothalamic hypocretin neurons. Symptomatic narcolepsy with low hypocretin level has been described in Ma antibody-associated encephalitis; however, the mechanisms underlying such an association remain unknown. OBSERVATIONS We described a 63-year-old man with clinical criteria for diencephalic encephalitis with sleepiness, cataplexy, hypocretin deficiency, and central hypothyroidism, together with brainstem encephalitis reflected by supranuclear ophtalmoparesis and rapid eye movement sleep behavior disorder with underlying abnormalities on brain magnetic resonance imaging. An autoimmune process was demonstrated by the detection of antibodies against Ma protein. Death occurred 4 months after disease onset without any tumor detected. Neuropathology, immunohistochemistry, and immunoreactivity results were compared with those obtained in idiopathic narcolepsy-cataplexy and with normal control brains. The principal findings revealed almost exclusive inflammation and tissue injury in the hypothalamus. The type of inflammatory reaction suggests cytotoxic CD8+ T lymphocytes being responsible for the induction of tissue injury. Inflammation was associated with complete loss of hypocretinergic neurons. Autoantibodies of the patient predominantly stained neurons in the hypothalamus and could be absorbed with Ma2. CONCLUSIONS AND RELEVANCE The encephalitic process, responsible for narcolepsy-cataplexy and hypocretin deficiency, reflects a CD8+ inflammatory-mediated response against hypocretin neurons.
    08/2013; 70(10). DOI:10.1001/jamaneurol.2013.2831
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    ABSTRACT: To determine the pathophysiologic features of progressive multifocal leukoencephalopathy (PML) associated with immune reconstitution inflammatory syndrome (PML-IRIS) in HIV-infected patients. In a cross-sectional study, we retrospectively analyzed 11 HIV-infected patients with a firm diagnosis of PML-IRIS. Brain biopsies were collected from 5 patients and their histopathologic features were compared to those of 4 HIV-infected patients with classic PML. PML-IRIS developed soon after initiation of antiretroviral therapy in late-presenting HIV-infected patients. The lesions from the 5 biopsied PML-IRIS patients were characterized by a reduction in the density of JC virus (JCV)-infected cells when compared to the 4 patients with PML (11.1 ± 3.2/mm(2) vs 51.2 ± 4.3/mm(2), p = 0.01). Comparing the 5 patients with PML-IRIS vs the 4 patients with PML, this correlated with an increased accumulation of CD8+ T cells (818.2 ± 192.8/mm(2) vs 52.5 ± 10.6/mm(2), p = 0.01), CD20+ B cells (33.4 ± 13.5/mm(2) vs 0.5 ± 0.5/mm(2), p = 0.01), and CD138+ plasma cells (177 ± 84.1/mm(2) vs 0.25 ± 0.25/mm(2), p = 0.01), while the number of CD68+ macrophages/microglia did not differ. The ratio between CD8+ T cells and JCV-infected cells was 70 times higher in the 5 patients with PML-IRIS. These findings indicate a clear relationship between an enhanced recruitment of CD8+ T cells and the associated control of the JCV infection. Our data provide in situ evidence that PML-IRIS brain lesions are enriched in cytotoxic CD8+ T cells that engage JCV-infected oligodendrocytes. This leads to a better control of JCV dissemination, but at the cost of oligodendrocyte cell death and demyelination.
    Neurology 08/2013; 81(11). DOI:10.1212/WNL.0b013e3182a43e6d · 8.30 Impact Factor
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    ABSTRACT: Accumulating evidence shows that T cells penetrate the central nervous system (CNS) parenchyma in several autoimmune, infectious, and degenerative neurological diseases. The structural and functional consequences for CNS neurons of their encounter with activated T cells have been investigated in several experimental systems, including ex vivo co-cultures, electrophysiology, and in vivo imaging. Here, we review the modalities of neuron/T cell interactions. We substantiate the contention that T cells are directly responsible for neuronal damage in a large number of neurological diseases and discuss mechanisms of neuronal damage mediated by distinct T cell subsets, the impact of which differs depending on the disease. Finally, we describe how a better understanding of the mechanisms at play offers new possibilities for therapeutic intervention.
    Trends in Neurosciences 03/2013; 36(6). DOI:10.1016/j.tins.2013.01.008 · 12.90 Impact Factor
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    ABSTRACT: An increase in IL-17-producing CD8(+) T (Tc17) cells has been reported in the peripheral blood of children with recent onset type 1 diabetes (T1D), but their contribution to disease pathogenesis is still unknown. To directly study the pathogenic potential of β cell-specific Tc17 cells, we used an experimental model of T1D based on the expression of the neo-self Ag hemagglutinin (HA) in the β cells of the pancreas. When transferred alone, the IL-17-producing HA-specific CD8(+) T cells homed to the pancreatic lymph nodes without causing any pancreatic infiltration or tissue destruction. When transferred together with small numbers of diabetogenic HA-specific CD4(+) T cells, a strikingly different phenotype developed. Under these conditions, Tc17 cells sustained disease progression, driving the destruction of β-islet cells, causing hyperglycemia and ultimately death. Disease progression did not correlate with functional or numerical alterations among the HA-specific CD4(+) T cells. Rather, the transferred CD8(+) T cells accumulated in the pancreatic islets and a considerable fraction converted, under the control of IL-12, to an IFN-γ-producing phenotype. Our data indicate that Tc17 cells are not diabetogenic but can potentiate a Th1-mediated disease. Plasticity of the Tc17 lineage is associated with transition to overt disease in this experimental model of T1D.
    The Journal of Immunology 08/2012; 189(6):3140-9. DOI:10.4049/jimmunol.1103111 · 5.36 Impact Factor
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    ABSTRACT: Human papillomaviruses (HPV) cause a variety of mucosal and skin lesions ranging from benign proliferations to invasive carcinomas. The clinical manifestations of infection are determined by host-related factors that define the natural anti-HPV barrier. Key elements of this barrier are the EVER1 and EVER2 proteins, as deficiency in either one of the EVER proteins leads to Epidermodysplasia Verruciformis (EV), a genodermatosis associated with HPV-induced skin carcinoma. Although EVERs have been shown to regulate zinc homeostasis in keratinocytes, their expression and function in other cell types that may participate to the anti-HPV barrier remain to be investigated. In this work, we demonstrate that EVER genes are expressed in different tissues, and most notably in lymphocytes. Interestingly, in contrast to the skin, where EVER2 transcripts are hardly detectable, EVER genes are both abundantly expressed in murine and human T cells. Activation of CD4+ and CD8+ T cells via the TCR triggers a rapid and profound decrease in EVER expression, accompanied by an accumulation of free Zn(2+) ions. Thus, EVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytes. Consistent with this hypothesis, we show that the concentration of Zn(2+) ions is elevated in lymphoblastoid cells or primary T cells from EVER2-deficient patients. Interestingly, we also show that Zn(2+) excess blocks T-cell activation and proliferation. Therefore, EVER proteins appear as key components of the activation-dependent regulation of Zn(2+) concentration in T cells. However, the impact of EVER-deficiency in T cells on EV pathogenesis remains to be elucidated.
    PLoS ONE 06/2012; 7(6):e39995. DOI:10.1371/journal.pone.0039995 · 3.53 Impact Factor
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    ABSTRACT: The immune reconstitution inflammatory syndrome (IRIS) is an important clinical complication in HIV-infected patients initiating antiretroviral therapy. This review focuses on the latest literature pertaining to the pathogenesis of IRIS. The clinical manifestations of IRIS are heterogeneous due to the variety of opportunistic infections that are associated with this inflammatory syndrome. However, the disproportionate inflammation is a defining hallmark for which common mechanisms are suspected. Lymphopenia-induced proliferation in the context of systemic immune activation, presence of high antigenic exposure and a wider availability of interleukin-7 contribute to the exacerbated immune response underlying IRIS. Defect in pathogen clearance by phagocytes might favor high pathogen burden, which in turn is thought to activate both innate immune cells and pathogen-specific T cells upon correction of the CD4 T-cell lymphopenia, predisposing to IRIS. This common scenario might be further invigorated by functional impairments among regulatory T cells. Further insight into the cellular mechanisms driving IRIS is urgently needed. Understanding the relative contribution of distinct effector and regulatory T-cell subsets, and innate immune components to IRIS is required to inspire future therapeutic approaches.
    Current Opinion in Infectious Diseases 06/2012; 25(3):312-20. DOI:10.1097/QCO.0b013e328352b664 · 5.03 Impact Factor
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    ABSTRACT: An increasing number of neurologic diseases is associated with autoimmunity. The immune effectors contributing to the pathogenesis of such diseases are often unclear. To explore whether self-reactive CD8 T cells could attack CNS neurons in vivo, we generated a mouse model in which the influenza virus hemagglutinin (HA) is expressed specifically in CNS neurons. Transfer of cytotoxic anti-HA CD8 T cells induced an acute but reversible encephalomyelitis in HA-expressing recipient mice. Unexpectedly, diabetes insipidus developed in surviving animals. This robust phenotype was associated with preferential accumulation of cytotoxic CD8 T cells in the hypothalamus, upregulation of MHC class I molecules, and destruction of vasopressin-expressing neurons. IFN-γ production by the pathogenic CD8 T cells was necessary for MHC class I upregulation by hypothalamic neurons and their destruction. This novel mouse model, in combination with related human data, supports the concept that autoreactive CD8 T cells can trigger central diabetes insipidus.
    The Journal of Immunology 04/2012; 188(10):4731-5. DOI:10.4049/jimmunol.1102998 · 5.36 Impact Factor
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    ABSTRACT: Spontaneous or chemically induced germline mutations, which lead to Mendelian phenotypes, are powerful tools to discover new genes and their functions. Here, we report an autosomal recessive mutation that occurred spontaneously in a Brown-Norway (BN) rat colony and was identified as causing marked T cell lymphopenia. This mutation was stabilized in a new rat strain, named BN(m) for "BN mutated." In BN(m) rats, we found that the T cell lymphopenia originated in the thymus, was intrinsic to CD4 T lymphocytes, and was associated with the development of an inflammatory bowel disease. Furthermore, we demonstrate that the suppressive activity of both peripheral and thymic CD4(+) CD25(bright) regulatory T cells (Treg) is defective in BN(m) rats. Complementation of mutant animals with BN Treg decreases disease incidence and severity, thus suggesting that the impaired Treg function is involved in the development of inflammatory bowel disease in BN(m) rats. Moreover, the cytokine profile of effector CD4 T cells is skewed toward Th2 and Th17 phenotypes in BN(m) rats. Linkage analysis and genetic dissection of the CD4 T cell lymphopenia in rats issued from BN(m)×DA crosses allowed the localization of the mutation on chromosome 1, within a 1.5 megabase interval. Gene expression and sequencing studies identified a frameshift mutation caused by a four-nucleotide insertion in the Themis gene, leading to its disruption. This result is the first to link Themis to the suppressive function of Treg and to suggest that, in Themis-deficient animals, defect of this function is involved in intestinal inflammation. Thus, this study highlights the importance of Themis as a new target gene that could participate in the pathogenesis of immune diseases characterized by chronic inflammation resulting from a defect in the Treg compartment.
    PLoS Genetics 01/2012; 8(1):e1002461. DOI:10.1371/journal.pgen.1002461 · 8.17 Impact Factor
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    ABSTRACT: Following infection of the central nervous system (CNS), the immune system is faced with the challenge of eliminating the pathogen without causing significant damage to neurons, which have limited capacities of renewal. In particular, it was thought that neurons were protected from direct attack by cytotoxic T lymphocytes (CTL) because they do not express major histocompatibility class I (MHC I) molecules, at least at steady state. To date, most of our current knowledge on the specifics of neuron-CTL interaction is based on studies artificially inducing MHC I expression on neurons, loading them with exogenous peptide and applying CTL clones or lines often differentiated in culture. Thus, much remains to be uncovered regarding the modalities of the interaction between infected neurons and antiviral CD8 T cells in the course of a natural disease. Here, we used the model of neuroinflammation caused by neurotropic Borna disease virus (BDV), in which virus-specific CTL have been demonstrated as the main immune effectors triggering disease. We tested the pathogenic properties of brain-isolated CD8 T cells against pure neuronal cultures infected with BDV. We observed that BDV infection of cortical neurons triggered a significant up regulation of MHC I molecules, rendering them susceptible to recognition by antiviral CTL, freshly isolated from the brains of acutely infected rats. Using real-time imaging, we analyzed the spatio-temporal relationships between neurons and CTL. Brain-isolated CTL exhibited a reduced mobility and established stable contacts with BDV-infected neurons, in an antigen- and MHC-dependent manner. This interaction induced rapid morphological changes of the neurons, without immediate killing or impairment of electrical activity. Early signs of neuronal apoptosis were detected only hours after this initial contact. Thus, our results show that infected neurons can be recognized efficiently by brain-isolated antiviral CD8 T cells and uncover the unusual modalities of CTL-induced neuronal damage.
    PLoS Pathogens 11/2011; 7(11):e1002393. DOI:10.1371/journal.ppat.1002393 · 8.06 Impact Factor

Publication Stats

8k Citations
1,156.19 Total Impact Points

Institutions

  • 2008–2015
    • University of Toulouse
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 2011–2014
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2000–2014
    • French Institute of Health and Medical Research
      • Toulouse Purpan Pathophysiology Center CPTP
      Lutetia Parisorum, Île-de-France, France
  • 1997–2014
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2006–2012
    • Paul Sabatier University - Toulouse III
      Tolosa de Llenguadoc, Midi-Pyrénées, France
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 2004
    • Centre Hospitalier Universitaire de Toulouse
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 1999–2003
    • Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
      Lutetia Parisorum, Île-de-France, France
    • Pierre and Marie Curie University - Paris 6
      Lutetia Parisorum, Île-de-France, France
  • 2001
    • University of Vienna
      • Institute of Neurophysiology
      Wien, Vienna, Austria
  • 1993–1998
    • Stanford University
      • • Department of Microbiology and Immunology
      • • Department of Medicine
      Palo Alto, California, United States
  • 1996
    • The Scripps Research Institute
      La Jolla, California, United States
  • 1995–1996
    • Stanford Medicine
      • Department of Microbiology and Immunology
      Stanford, California, United States
    • Harvard University
      Cambridge, Massachusetts, United States