The role of MAZR during cytotoxic T cell differentiation

How common thymic progenitors differentiate into the two functionally distinct helper and cytotoxic T cells is one of the fundamental questions in the field of immunology. The zinc finger protein MAZR has been identified as an important negative regulator of the activation of the Cd8 gene complex during the early stages of thymocyte development. Recently, we revealed that MAZR is part of the transcription network that controls cell fate decision. We demonstrated that MAZR represses ThPOK expression in MHC class I-signaled thymocytes, possibly via binding to the Thpok silencer, and thereby preventing redirected differentiation of these thymocytes into the helper lineage. However, the detailed mechanism of how MAZR regulates ThPOK expression during T cell development remains to be elucidated. Furthermore, the role of MAZR in peripheral CD8+ T cells is largely unexplored. In this application, I will investigate the role of potential MAZR/Runx1 interaction in ThPOK repression and cell fate decision of DP thymocytes. In addition, I will elucidate the role of MAZR in ThPOK repression in peripheral CD8+ T cells, particularly from an epigenetic point of view, and will perform a comprehensive analysis of function of MAZR-deficient CD8+ T cells. I anticipate that these studies will further clarify how MAZR is integrated in the transcriptional program of cytotoxic T cell differentiation, and that thereby will advance our understanding of T cell development at a molecular level.

With the support of the FWF project P23669, we revealed novel transcriptional mechanisms controlling T cell development. T cells are an important component of the adaptive immune system, and mainly subdivided into two functionally distinct subsets: helper T cells and cytotoxic T cells. These two T cell subsets develop from common progenitors in thymus, and a complex transcription factor network orchestrates the differentiation process. In the P23669 project we revealed that the two transcription factors, MAZR and Runx, synergistically repress the two hallmark proteins of helper T cells (i.e. ThPOK and CD4), thereby supporting the cytotoxic T cell development of thymic progenitors. Moreover, our data demonstrate that MAZR is also required for the maintenance of ThPOK repression in cytotoxic T cells. Thus, our study provides new insight into the transcriptional network controlling the helper-versus-cytotoxic cell fate choice and the lineage-specific gene regulation. How bi- or multi-potential common progenitors differentiate into functionally distinct cells is a fundamental question in the field of immunology as well as developmental and cancer biology. Therefore, by using T cell development as a model system, our study might have an impact on the research field of hematopoiesis as well as embryogenesis and oncogenesis.