title: Cytomegalovirus infection exacerbates autoimmune mediated neuroinflammation.
abstract: Cytomegalovirus (CMV) is a latent virus which causes chronic activation of the immune system. Here, we demonstrate that cytotoxic and pro-inflammatory CD4+CD28nullT cells are only present in CMV seropositive donors and that CMV-specific Immunoglobulin (Ig) G titers correlate with the percentage of these cells. In vitro stimulation of peripheral blood mononuclear cells with CMVpp65 peptide resulted in the expansion of pre-existing CD4+CD28nullT cells. In vivo, we observed de novo formation, as well as expansion of CD4+CD28nullT cells in two different chronic inflammation models, namely the murine CMV (MCMV) model and the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis (MS). In EAE, the percentage of peripheral CD4+CD28nullT cells correlated with disease severity. Pre-exposure to MCMV further aggravated EAE symptoms, which was paralleled by peripheral expansion of CD4+CD28nullT cells, increased splenocyte MOG reactivity and higher levels of spinal cord demyelination. Cytotoxic CD4+T cells were identified in demyelinated spinal cord regions, suggesting that peripherally expanded CD4+CD28nullT cells migrate towards the central nervous system to inflict damage. Taken together, we demonstrate that CMV drives the expansion of CD4+CD28nullT cells, thereby boosting the activation of disease-specific CD4+T cells and aggravating autoimmune mediated inflammation and demyelination.
authors.affiliation: Hasselt University, Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, Diepenbeek, Belgium.
authors.forename: Marjan
authors.initials: M
authors.lastname: Vanheusden
authors.affiliation: Hasselt University, Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, Diepenbeek, Belgium.
authors.forename: Bieke
authors.initials: B
authors.lastname: Broux
authors.affiliation: Leiden University Medical Centre, Department of Immunohematology and Blood Transfusion, Leiden, The Netherlands.
authors.forename: Suzanne P M
authors.initials: SPM
authors.lastname: Welten
authors.affiliation: Hasselt University, Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, Diepenbeek, Belgium.
authors.forename: Liesbet M
authors.initials: LM
authors.lastname: Peeters
authors.affiliation: Leiden University Medical Centre, Department of Immunohematology and Blood Transfusion, Leiden, The Netherlands.
authors.forename: Eleni
authors.initials: E
authors.lastname: Panagioti
authors.affiliation: Hasselt University, Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, Diepenbeek, Belgium.|Rehabilitation and Multiple Sclerosis Centre, Overpelt, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Van Wijmeersch
authors.affiliation: Hasselt University, Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, Diepenbeek, Belgium.
authors.forename: Veerle
authors.initials: V
authors.lastname: Somers
authors.affiliation: Hasselt University, Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, Diepenbeek, Belgium.
authors.forename: Piet
authors.initials: P
authors.lastname: Stinissen
authors.affiliation: Leiden University Medical Centre, Department of Immunohematology and Blood Transfusion, Leiden, The Netherlands.
authors.forename: Ramon
authors.initials: R
authors.lastname: Arens
authors.affiliation: Hasselt University, Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, Diepenbeek, Belgium. niels.hellings@uhasselt.be.
authors.forename: Niels
authors.initials: N
authors.lastname: Hellings
mesh_terms: D000328:Adult; D000818:Animals; D000941:Antigens / Q000276:immunology; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000150:complications / Q000276:immunology* / Q000821:virology*; D003711:Demyelinating Diseases; D004195:Disease Models, Animal; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000150:complications / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000150:complications / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D012720:Severity of Illness Index; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
chemical_list: D000941:Antigens