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Open Access Highly Accessed Research article

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

Sara Martinez-Pasamar1, Elena Abad2, Beatriz Moreno1, Nieves Velez de Mendizabal3, Ivan Martinez-Forero4, Jordi Garcia-Ojalvo2 and Pablo Villoslada1*

Author Affiliations

1 Center of Neuroimmunology, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Hospital Clinic of Barcelona, Barcelona, Spain

2 Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain

3 School of Medicine and Indiana Clinical and Translational Sciences Institute, Indiana University, Indianapolis, IN, USA

4 Hospital Pablo Tobón Uribe, Medellin, Colombia

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BMC Systems Biology 2013, 7:34  doi:10.1186/1752-0509-7-34

Published: 26 April 2013

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.

Keywords:
T cells; Effector; Regulatory; B cells; Dynamics; Autoimmunity; Multiple sclerosis; Systems biology; Immunotherapy; Anti-CD20