Tolerance

Immune Tolerance Network    Indices of Tolerance    T regulatory cells

Central Tolerance:

Central tolerance occurs in the thymus. DCs play an important role in the self-nonself distinction imposed by the developing thymus where they present self antigens to developing T cells and delete lymphocytes with autoreactivity.

Peripheral Tolerance:

Many self-antigens cannot access the thymus, while others are expressed later in life. Thus there is a need for peripheral tolerance which occurs in the lymphoid organs by the induction of T cell anergy (unresponsiveness) rather than deletion. The development of peripheral tolerance involves immature DCs.

A number of mechanisms have been proposed to account for the maintenance of peripheral self-tolerance, including induction of T cell anergy, T cell deletion and immunological ignorance. Although these passive mechanisms certainly contribute, it is likely that regulation occurs by regulatory T cells.

Oral Tolerance:

Oral tolerance is the state of systemic Ag-specific hyporesponsiveness induced by the oral administration of soluble Ags. The physiological role of oral tolerance is thought to be the prevention of hypersensitivity to food Ags and is a representative form of peripheral tolerance against non-self-Ags under physiological conditions.

Oral tolerance is mediated by T cells. 3 mechanisms have been proposed to be involved in the induction of oral tolerance:

• unpresponsiveness of T cells to specific Ags (anergy)
• immune suppression by regulatory T cells that produce TGF-β or IL-10
• elimination of Ag-specific T cells via apoptosis. (clonal deletion)

Role of Dendritic cells in Tolerance:

LPS Tolerance: Mechanisms of LPS tolerance have traditionally been studied using inflammatory gene products as a read-out (TNF, IL-6, IL-1 etc). Variety of negative regulators are responsible for inhibition in signalling. Tolerance is gene-specific (ex. IL-6 vs CRAMP. CRAMP actually upregulates in macrophages upon second exposure to LPS.) So promoter specific changes in gene expression. Some promoters can actually become sensitized and even more active. So two classes of genes (pro-inflammatory vs. anti-microbial). Half genes are tolerizable and one half non-tolerizable which behave like CRAMP.

In naive cells RNA PolII is not recruited. Gene specific differences have to do with chromatin modifications. These differences are not signal specific. In naive cells, both promoters have active histone modification. When treat macrophages with TSA (histone deacytylation) then tolerant cells which normally do not produce IL-6 all of suddenly do produce IL-6.

Nucleosome remodling is differentially regulated at toelrazalbe and non-tolerizable promoters due also to chromatin remodeling. In tolerance cells Brg is not recruited.