Research Report - Nikolaus-Fiebiger-Zentrum für Molekulare Medizin

Research
Our research is focussed on the function of Dendritic cell subpopulations in the
process of induction of immunity and maintenance of peripheral tolerance. Dendritic
cells are very important antigen presenting cells. We are especially interested in the
analysis of antigen uptake, antigen processing and antigen presentation by Dendritic
cells, if and how Dendritic cell subpopulations differ in antigen processing and
presentation, and how Dendritic cell subpopulations migrate in the lymphoid tissues
when they have encountered their antigens under immunizing and tolerizing
conditions. Moreover, to understand antigen processing and presentation
mechanisms we focus on the responding T cells. Depending on the Dendritic cell
subpopulation we found that different Dendritic cell subpopulations can induce
different T cell responses in vivo (Dudziak et al., 2007). These findings will have
important implications in the development of new therapeutic vaccines.
Dendritic cells and antigen targeting
Dendritic cells maintain peripheral tolerance and induce immunity
The immune system controls invading pathogenic organisms by innate and adaptive
immune mechanisms. To enable recognition of virtually any antigen, developing B
and T cells randomly rearrange their receptors to produce unique clones with a wide
variety of specificities. It is well accepted that this also leads to the generation of
receptors that can recognize ‘self’ antigens. By central tolerance mechanisms at
several checkpoints self reactive B cells are deleted in the bone marrow whereas self
reactive T cells undergo negative selection mechanisms in the thymus where they
are either deleted or undergo anergic mechanisms. As some of the T cells can
escape negative selection in the thymus, checkpoints in the periphery have to exist to
prevent autoimmune reactions by those potentially self-reactive T cells. Only recently
it became clear that DCs which are essential for the induction of adaptive immune
responses are also key players not only for the maintenance of central tolerance but
also for the maintenance of peripheral tolerance.
Dendritic cells (DCs) are the most important antigen presenting cells in the immune
system. In non-lymphoid organs DCs act as sentinels and take up and process
antigens from the periphery (skin, airways, intestine, interstitial spaces of various
organs). Antigen loaded DCs migrate to the lymphoid tissues and interact with
antigen-specific T cells. Besides the uptake of soluble antigens, DCs are also able to
ingest apoptotic cells, tumor cells, or infected cells to present their antigen. The
induction of peripheral tolerance or immunity depends on the DC differentiation state.
In the steady-state immature DCs express low levels of CD80, CD86 or MHC class II
molecules on their cell surface. Recognition of the MHC peptide complex by a T cell
in the steady-state causes deletion or anergy of self reactive T cells after an initial
phase of proliferation. This process is resulting in peripheral tolerance (Dudziak et al.,
2007, Dudziak, 2009).
In contrast, during a microbial or viral infection antigen uptake is paralleled by DC
activation and maturation. In this process pattern-recognition receptors (PRRs)
expressed on DCs, such as Toll-like receptors (TLRs) and proteins of the C-type
lectin receptor family, recognize conserved parts of pathogens such as lipids, sugar
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