Abstract
Young T-lymphocytes undergo two central selection steps before they enter the pool of immuno-competent cells. In the thymus it is ensured that emerging T cells only recognize foreign peptides in conjunction with self-MHC (major histocompatibility complex), and that they can distinguish between self and foreign peptides. This first process is termed positive selection, the latter is known as negative selection. For both events self-MHC as well as self peptides are needed. Several groups have tried to describe the characteristics of such a peptide ligand. Until now no definitive description of such a protein fragment has been made due to the vast number of peptides possibly binding to one MHC molecule. Recently a new transgenic mouse model was established permitting the analysis of such self peptides. In the C10.4 TCRtrans+ model the transgenic TCR is selected by the non classical MHC molecule H2-M3, in conjunction with the physiological peptide ND1. The ND1 peptide encodes for the NADH-Dehydrogenase subunit 1 of the mitochondrial genome. Using a fetal thymic organ culture system (FTOC) we were able to show that ND1 induced positive selection in a defined, yet narrow window of peptide concentrations. I was further able to show that ND1 is recognized by mature C10.4 TCRtrans+ T-cells as a weak agonist. The Listeria monocytogenes peptide however is a strong agonist for mature C10.4 TCRtrans+ T-cells. This peptide as well could induce positive selection, however at much lower peptide concentration. With increased peptide concentrations, and therefore increased epitope densities, both peptides were only able to select partial functional T-cells. I concluded that positive selection is driven by a small window of avidity. I further investigated the specificity in this model system. At low peptide concentration shortening of the ND1 Peptide, as well as the mutation of surface exposed side chains, altered positive selection. I concluded that under physiological conditions positive selection of C10.4 TCRtrans+ T-cells is highly specific and occurs at low epitope densities. The definition of a naturally occurring peptides able to select a T-cell clone, combined with the knowledge about peptide requirements for a productive TCR-MHC interaction allows us to imagine how specific T-cells could be raised in vitro or in vivo. The production of specific T-cells would be a useful strategy to control viral or bacterial infections. The human immunodeficiency virus for example selectively attacks T-lymphocytes. Specific T-cells could protect and final rid the body from infected cells. One could further imagine that tumor specific T-cells find malignant cells, that either overexpress self-peptides, or present mutants of self-peptides. Taken the sequence of a self-peptide and the activating cognate peptide together the prediction of a selecting peptide motif is within reach.
Author and committee
dc:creator, dc:contributor.*- Author
-
- Irion, Stefan
Identifiers
dc:identifier.*- Identifier
- hdl:10900/43803