Epigenetic and Transcriptional Regulation of CD8

The majority of thymus-derived TCRaß-positive T cells express either the CD4 or the CD8 coreceptor molecules. CD4-expressing cells have a helper phenotype, and express TCRs specific for MHC class II, whereas CD8 + T cells have a cytotoxic phenotype and are MHC class I restricted. These single-positive (SP) cells develop in the thymus from common double-positive (DP) progenitor cells that express both CD4 and CD8, through positive selection of those cells that have TCRs with appropriate avidity for MHC/peptide complexes. The molecular mechanisms that regulate the development of double-positive (DP) thymocytes into the CD4 + helper and CD8 + cytotoxic T cell lineage are not well described. Since there is coupling of CD4 and CD8 coreceptor expression with the functional programs of mature T cells, common factors may be involved both in the transcriptional regulation of the coreceptors and in the activation of T helper or T cytotoxic programs. Therefore, understanding the regulation of CD4 and CD8 gene expression might not only provide insight into transcriptional control mechanisms during T cell development, but also may help to explain the molecular basis of lineage commitment and function. Several developmental stage-, subset- and lineage-specific CD8 enhancers have been recently identified by transgenic reporter analyses. Within this FWF project we are trying to identify the trans-acting factors that interact with the various cis-regulatory elements. We will use part of the CD8 enhancer sequences as molecular baits to isolate the binding factors. The function of the isolated factors in the regulation of CD8 expression and during T cell development will then be analyzed by approaches that include retroviral-mediated gene transduction approaches and/or mouse molecular genetics tools.

One of our long-term research interests is to understand molecular mechanisms that link epigenetic gene regulation with cell fate specifications during T cell development. The majority of mature T cells express either CD4 or CD8, glycoproteins that serve as coreceptors for the T cell receptor. The former constitute the helper T cell lineage, while the latter display a cytotoxic phenotype. These single-positive (SP) cells develop in the thymus from a common CD4+CD8+ double-positive (DP) progenitor cell expressing both CD4 and CD8. It has been shown that the functional phenotype of the differentiated T cell lineage correlates with the expression of the coreceptor molecules. Thus, factors regulating the transcription of CD4 and CD8 may also be involved in directing the cell fate of a DP thymocyte towards the helper or cytotoxic lineage, respectively. Therefore, the identification and characterization of cis-regulatory elements and trans-acting factors involved in the epigenetic and transcriptional regulation of the coreceptor molecules may not only provide insight into transcriptional control mechanisms during T cell development, but may also help to understand the molecular basis of CD4/CD8 lineage commitment. Our laboratory is studying the regulation of CD8 coreceptor expression, a key molecule in the immune system for the development of the cytotoxic T cell lineage. CD8 coreceptor expression is tightly regulated during thymocyte development by the activity of at least five different cis-regulatory elements (the so-called Cd8 enhancers). With support of the FWF (Project P16708) we recently linked Cd8 enhancer function with chromatin remodelling and demonstrated epigenetic control of the Cd8 gene complex. We have further identified that the zinc finger protein MAZR is an important regulator of CD8 expression.