Dynamic cross-regulation of antigen-specific effector and regulatory T cell subpopulations and microglia in brain autoimmunity

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• dc.contributor.author Martínez Pasamar, Saraca
• dc.contributor.author Abad Adan, Elenaca
• dc.contributor.author Moreno, Beatrizca
• dc.contributor.author Vélez de Mendizábal, Nievesca
• dc.contributor.author Martínez Forero, Ivanca
• dc.contributor.author García Ojalvo, Jordica
• dc.contributor.author Villoslada, Pabloca
• dc.date.accessioned 2015-03-17T10:43:01Z
• dc.date.available 2015-03-17T10:43:01Z
• dc.date.issued 2013ca
• dc.description.abstract Background: Multiple Sclerosis (MS) is considered a T-cell-mediated autoimmune disease with a prototypical oscillatory behavior, as evidenced by the presence of clinical relapses. Understanding the dynamics of immune cells governing the course of MS, therefore, has many implications for immunotherapy. Here, we used flow cytometry to analyze the time-dependent behavior of antigen-specific effector (Teff) and regulatory (Treg) T cells and microglia in mice model of MS, Experimental Autoimmune Encephalomyelitis (EAE), and compared the observations with a mathematical cross-regulation model of T-cell dynamics in autoimmune disease. Results: We found that Teff and Treg cells specific to myelin olygodendrocyte glycoprotein (MOG) developed coupled oscillatory dynamics with a 4- to 5-day period and decreasing amplitude that was always higher for the Teff populations, in agreement with the mathematical model. Microglia activation followed the oscillations of MOG-specific Teff cells in the secondary lymphoid organs, but they were activated before MOG-specific T-cell peaks in the CNS. Finally, we assessed the role of B-cell depletion induced by anti-CD20 therapy in the dynamics of T cells in an EAE model with more severe disease after therapy. We observed that B-cell depletion decreases Teff expansion, although its oscillatory behavior persists. However, the effect of B cell depletion was more significant in the Treg population within the CNS, which matched with activation of microglia and worsening of the disease. Mathematical modeling of T-cell cross-regulation after anti-CD20 therapy suggests that B-cell depletion may influence the dynamics of T cells by fine-tuning their activation. Conclusions: The oscillatory dynamics of T-cells have an intrinsic origin in the physiological regulation of the adaptive immune response, which influences both disease phenotype and response to immunotherapy.en
• dc.description.sponsorship This work was supported in part by the Spanish network of excellence in MS of the Instituto de Salud Carlos III, Spain to PV and JGO (RD07/0060), by grant FIS-PI12/01823, the European Commission 7FP (CombiMS, contract grant: 305397), and by an unrestricted grant from Roche to PV; a grant of the Ministerio de Ciencia e Innovación (Spain, project FIS2009-13360) and by the ICREA Academia program to JGOen
• dc.format.mimetype application/pdfca
• dc.identifier.citation Martinez-Pasamar S, Abad E, Moreno B, Velez de Mendizabal N, Martinez-Forero I, Garcia-Ojalvo J, Villoslada P. Dynamic cross-regulation of antigen-specific effector and regulatory T cell subpopulations and microglia in brain autoimmunity. BMC Systems Biology. 2013; 7: 34. DOI 10.1186/1752-0509-7-34ca
• dc.identifier.doi http://dx.doi.org/10.1186/1752-0509-7-34
• dc.identifier.issn 1752-0509ca
• dc.identifier.uri http://hdl.handle.net/10230/23205
• dc.language.iso engca
• dc.publisher BioMed Centralca
• dc.relation.ispartof BMC Systems Biology. 2013; 7: 34
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/305397
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/FIS2009-13360
• dc.rights © 2013 Martinez-Pasamar et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.ca
• dc.rights.accessRights info:eu-repo/semantics/openAccessca
• dc.rights.uri http://creativecommons.org/licenses/by/2.0
• dc.subject.keyword T cellsen
• dc.subject.keyword Effectoren
• dc.subject.keyword Regulatoryen
• dc.subject.keyword B cellsen
• dc.subject.keyword Dynamicsen
• dc.subject.keyword Autoimmunityen
• dc.subject.keyword Multiple sclerosisen
• dc.subject.keyword Systems biologyen
• dc.subject.keyword Immunotherapyen
• dc.subject.keyword Anti-CD20en
• dc.subject.other Antígensca
• dc.subject.other Immunologiaca
• dc.subject.other Esclerosi múltipleca
• dc.title Dynamic cross-regulation of antigen-specific effector and regulatory T cell subpopulations and microglia in brain autoimmunityen
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/publishedVersionca