Community Research and Development Information Service - CORDIS

FP7

Peptide diversity Result In Brief

Project reference: 328866
Funded under: FP7-PEOPLE
Country: Germany

A step closer to understanding autoimmunity

A European study investigated the molecular determinants of T cell selection during development. Results could help scientists comprehend the causal links with autoimmunity.
A step closer to understanding autoimmunity
Immune-deficiencies and autoimmunity are two sides of the same coin: an impaired selection of functional and self-tolerant T cells. Although scientists know the cause of these disorders, they fail to comprehend how the same MHC/peptide complexes can promote either survival or apoptosis of T cells. As a result, it is necessary to decipher the nature of these MHC/peptide complexes and delineate the antigen processing pathways they follow.

The scope of the EU-funded PEPTIDE DIVERSITY (Diversity of MHC/peptide complexes in thymic compartments and their role in shaping T cell repertoire) project was to investigate how distinct thymic antigen presenting cells (APCs) mediate positive selection and tolerance induction. The underlying hypothesis was that the antigen processing pathways differed among the different APCs.

In this context, researchers focused their experimental plan on the differential expression of the proteolytic enzymes implicated in antigen processing and loading onto MHC molecules. In particular, they investigated mice lacking cathepsin L, the lysosomal protease expressed in cortical thymic epithelial cells (cTECs). These animals presented a severe loss of CD4 T cells due to defects in thymocyte development and an arrest of CD4 T cells at the immature stage. Peripheral T cells had a greater ratio of regulatory to effector T cells that was not due to excessive negative selection in the thymus.

To examine the positive selection of T cells, researchers utilised a panel of T cell receptor (TCR) transgenic mice where all CD4 T cells were specific for a defined antigen antigen. They observed that positive selection of these CD4 T cells in cathepsin L deficient animals was impaired. Furthermore, T cells educated on cathepsin L deficient thymus could not provide efficient help to B cells during immune responses against pathogens.

The PEPTIDE DIVERSITY findings provided important insight into the mechanism of T cell development and brought scientists a step closer to comprehending the selection of immuno-competent and self-tolerant T cells. This is expected to pave the way for the development of new pharmacological therapies against auto-immunity or immune-deficiencies.

Related information

Keywords

Autoimmunity, immune-deficiencies, T cell, MHC, cathepsin
Record Number: 181162 / Last updated on: 2016-05-10
Domain: Biology, Medicine