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Key factor for T-cell formation discovered

(Vienna, 12 April 2010) One major factor in the formation of white blood cells which controls the development of T-cells has been identified by scientists from the laboratory of Univ.-Prof. Mag. Dr. Wilfried Ellmeier. Related findings have now been published in the renowned specialist journal "Nature Immunology".

T-cells belong to the group of white blood cells and fulfil major functions in the immune system. They can be subdivided into two main types: CD4-positive T "helper" cells and CD8-positive cytotoxic T-cells. Both T-cell types develop in the thymus from common progenitor cells, the so-called CD4 and CD8 double-positive (DP) thymocytes. When does a T helper cell develop from a progenitor cell, when a cytotoxic T-cell, and which factors play a role in this process? These are some of the many key issues that basic immunological research focuses on and that fascinate many scientists, because ultimately it is also important to decipher fundamental biological and immunological processes.

One major contribution to this topic has now been supplied by the Division of Immunobiology headed by Univ. Prof. Dr. Wilfried Ellmeier at the Institute of Immunology (Centre for Pathophysiology, Infectiology and Immunology). Within the framework of a project that was financed by the Austrian Science Fund FWF it was shown that the transcription factor MAZR is involved in the decision of whether a progenitor cell becomes a CD4+ or a CD8+ T-cell. In a previous study the working group headed by Wilfried Ellmeier was able to demonstrate that MAZR regulates the expression of CD8, an important molecule of cytotoxic T-cells (Bilic et al., Nature Immunology, 2006). In the current study, which was conducted by Dr. Shinya Sakaguchi within the framework of his dissertation at the Division of Immunobiology, it was shown by establishing a mouse-model system that a reprogramming of developing CD8+ cytotoxic T-cells takes place in CD4+ helper T-cells if MAZR is switched off in DP thymocytes.

MAZR ModellIn recent years it has already been possible to identify transcription factors and transcriptional networks that regulate these "helper-versus-cytotoxic" T-cell decisions. One major transcription factor is Th-POK, a "master regulator" of the CD4+ helper T-cell development. Activation of Th-POK causes CD4+ T-cell development and its inhibition is necessary for CD8+ T-cell differentiation. But how Th-POK itself is regulated and which molecules and factors are involved in this process is only described in part.

At molecular level it has been possible to demonstrate in a large number of experiments conducted in collaboration with Dr. Ichrio Taniuchi from the RIKEN Center of Allergy and Immunology (Yokohama, Japan) that MAZR regulates the expression of Th-POK. Where MAZR is absent, Th-POK is switched on in a part of the DP thymocytes and this has the result that potential CD8+ T-cells suddenly become CD4+ helper T-cells.

"Our work has shown that MAZR suppresses the expression of Th-POK in emerging CD8+ cytotoxic T-cells and MAZR therefore plays a central and important regulatory function during T-cell development," explains Wilfried Ellmeier. "Additional studies will show whether our findings could also be of major importance for the investigation and treatment of immune diseases."

» S. Sakaguchi, M. Hombauer, I. Bilic, Y. Naoe, A. Schebesta, I. Taniuchi and W. Ellmeier: “The zinc-finger protein MAZR is part of the transcription factor network that controls the CD4-versus-CD8 lineage fate of double-positive thymocytes.” Nature Immunology, Published online 11 April 2010. doi:10.1038/ni.1860