Focus
Our group investigates the role of B and T cells in autoimmune and infectious diseases with particular emphasis on the characterization of novel pro-inflammatory and anti-inflammatory B cell as well as plasma cell subsets.
Introduction
The adaptive immune system plays a critical role in the defense against pathogens. Patients presenting with genetic deficiencies resulting in abnormal development or function of T or B lymphocytes are highly susceptible to infectious diseases, and the vast majority of successful vaccines provides protection through the generation of memory lymphocytes including in particular memory B cells and memory plasma cells. However, the adaptive immune system can also cause severe immunopathology when inappropriately reacting against self-antigens or components of the environment, which can lead to autoimmune diseases or allergies, respectively. The activation of such unwanted immune responses is normally controlled by the indexation of lymphocyte activation on signals produced upon the detection of pathogen-associated molecules through the innate immune system, and by the continuous activity of regulatory lymphocytes preventing the activation of potentially pathogenic lymphocytes. These include CD4+Foxp3+ T regulatory cells, and regulatory plasma cells producing the anti-inflammatory cytokines IL-10 and IL-35. Our group studies the antigen-recognition properties of these cells, their ontogeny, their life-span, and their mode of action in health and disease. Our long-term goal is to develop novel strategies to manipulate these cells therapeutically based on the knowledge gained from our basic studies.
Research objectives
Our objectives are to contribute to the identification of the distinctive features controlling the development, maintenance, activation, and function of selected lymphocyte subsets of possible importance in health and disease. We are currently aiming at the characterization of cytokine-producing B cells, with a focus on those expressing the pro-inflammatory mediator IL-6, which have a key role as drivers of autoimmune pathology in diseases such as multiple sclerosis (MS), and those secreting the anti-inflammatory cytokines IL-10 and IL-35, which are impaired in autoimmune disorders, for instance in MS. Our goals are to clarify the development of these cells, their distinctive phenotypic features and antigen-recognition properties, the molecular mechanisms controlling their expression of cytokine, and their life-span as well as potential contribution to immunological memory. In a second project, we are aiming at identifying the molecular mechanisms controlling the life-span of plasma cells in the bone marrow where they can persist for a lifetime in particular immune responses. Finally, we are pursuing our work on the distinctive antigen recognition properties of autoreactive CD4+Foxp3+ T regulatory cells in comparison to autoreactive CD4+Foxp3- T cells, and on the molecular mechanisms controlling the protective value of the former in adoptive cell therapy against autoimmune diseases.
5 main publications
- Kieback E, et al. (2016) Thymus-Derived Regulatory T Cells Are Positively Selected on Natural Self-Antigen through Cognate Interactions of High Functional Avidity. Immunity 44(5):1114-1126.
- Li R, et al. (2015) Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci Transl Med 7(310):310ra166.
- Shen P & Fillatreau S (2015) Antibody-independent functions of B cells: a focus on cytokines. Nat Rev Immunol 15(7):441-451.
- Shen P, et al. (2014) IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 507(7492):366-370.
- Barr TA, et al. (2012) B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells. J Exp Med 209(5):1001-1010.
