Abstracts (complete list) - Wissenschaft Online

Maria Papatriantafyllou, Thilo Oelert, Günter Hämmerling, Bernd Arnold
MOLECULAR MECHANISMS OF PERIPHERAL CD8 T CELL
TOLERANCE
Clarifying the mechanisms of immunological tolerance is essential for the development
of effective therapies against cancer and autoimmunity. Central tolerance is achieved by
clonal deletion or the intrathymic induction of regulatory T cells. However, not all
autoreactive T cells are eliminated in the thymus and self-tolerance is further assured
by rendering autoreactive T cells that escape negative selection, tolerant in the
periphery. In our model a regulatory CD8 + CD25 - T cell population mediates peripheral
tolerance against self antigen. In neonates CD8 T cells pass through the endothelium
and have access to tissues (e.g. liver, skin). Those that have specific T cell receptor
(TCR) for autoantigens are rendered tolerant and suppress immune response against
self during the adult phase. In detail, transgenic mice express anti-Kb TCR (Des-TCR) in
CD8 T cells and the Kb molecule under the control of the 2,4Ker-IV promoter in the skin
but not in the thymus (DesTCRxKerKb mice). As a result, the CD8 T cells recognize the
antigen in the periphery during the neonatal phase, become tolerant and suppress the
immune response against Kb self antigen. This model is being used to investigate the
gene expression pattern of tolerant CD8 T cells and clarify the molecular mechanisms of
peripheral CD8 T cell tolerance. Either naïve, activated or tolerant CD8 T cells are sorted
from the spleen of DesTCR mice or Des-TCRxKerKb mice respectively and their gene
expression profile is determined with the oligonucleotide microarrays from Affymetrix.
According to the microarray data genes that are involved in the suppression of the
immune response are upregulated in tolerant CD8 T cells, such as components of the
TGF-β1 and Notch pathways. The most prominent candidates are under investigation
and their contribution to CD8 T cell tolerance will be discussed.