Fredrik Ivars, PhD, Senior lecturer, Group Leader
The focus of our group is immunoregulation, with a particular interest in mechanisms involved peripheral T cell tolerance. The immune system produces T cells that may react to body components (auto-reactive T cells), unless the cells are silenced by various peripheral tolerance mechanisms. These mechanisms involve the elimination of reactive T cells (deletion), inactivation of reactive T cells (anergy) and inhibition of the reactive T cells by regulatory T cells (Treg; suppression). Auto-reactive T cells are thought to encounter the body components (or self-antigens) in lymphoid organs, presented on dendritic cells (DC).
During an infection, the presenting DCs will become activated by microbial components and will activate the antigen-specific T cells such that the latter will become effector cells capable of eliminating the infection. However, auto-reactive T cells encounter self-antigens under steady state conditions, in the absence of infection, and hence the self-antigens are presented by ”resting” DCs. As the result of such defective stimulation, the auto-reactive T cells may either be deleted or become anergic rather than developing to effector cells. Under these conditions, auto-reactive T cells may alternatively develop into Treg and these cells may subsequently inhibit the activation and/or the effector functions of auto-reactive T cells. Hence, in general no destructive immune response will be induced to self-antigens and tissue integrity will be preserved.
There are several kinds of Treg. The CD4+ CD25+ or natural Treg are produced both in the thymus and in the periphery. This population is however best defined by the expression of the Foxp3 protein. Another kind of Treg, the Tr1 cells, develop outside the thymus, do not express Foxp3 and are functionally distinct from the natural Treg.
It is well established that Foxp3 expressing natural Treg can be induced in peripheral lymphoid organs. The mechanism of induction is however unknown. To better understand the mechanism of this event we are currently investigating the induction of these cells using T cell transfer models with a particular focus on induction in the gut associated lymphoid tissue. In another model we study the induction of Tr1-like Treg. This model is based on the repetitive stimulation of CD4+ T cells with a foreign protein antigen, mimicking the stimulation of peripheral T cells by auto-antigens. In this model we address the role various DC populations in the induction. In a third model we study the role of Treg in establishment of tolerance to vascularized allogeneic heart transplants. Tolerance is established by treatment of transplanted animals with antibodies blocking crucial membrane molecules on DC. The role of Treg in tolerance in this model is studied both in lymphoid organs and locally in the transplanted heart tissue.
We are currently also initiating a project aiming at understanding the role of natural Treg in regulating inflammation at sites of infection and in autoimmune disease. We will study how these cells will influence DCs and macrophage functions locally with a focus on the expression of inflammation regulating enzymes.
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Last modified: 2012-02-08
